EP1530477A1 - COMBINATION THERAPY WITH p38 MAP KINASE INHIBITORS AND THEIR PHARMACEUTICAL COMPOSITIONS - Google Patents

COMBINATION THERAPY WITH p38 MAP KINASE INHIBITORS AND THEIR PHARMACEUTICAL COMPOSITIONS

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Publication number
EP1530477A1
EP1530477A1 EP03785255A EP03785255A EP1530477A1 EP 1530477 A1 EP1530477 A1 EP 1530477A1 EP 03785255 A EP03785255 A EP 03785255A EP 03785255 A EP03785255 A EP 03785255A EP 1530477 A1 EP1530477 A1 EP 1530477A1
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European Patent Office
Prior art keywords
naphthalen
urea
butyl
tert
pyridin
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EP03785255A
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German (de)
French (fr)
Inventor
S. Boehringer Ingelheim Pharma SIMIANER
P. Boehringer Ingelheim France BILBAULT
M. L. Boehringer Ingelheim Pharma. Inc. CAPPOLA
Susan L. Boehringer Ingelheim Pharma. Inc. WAY
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Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim France SAS
Boehringer Ingelheim Pharmaceuticals Inc
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Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim France SAS
Boehringer Ingelheim Pharmaceuticals Inc
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Publication of EP1530477A1 publication Critical patent/EP1530477A1/en
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to p38 kinase inhibitors in combination with other active ingredients, their pharmaceutical compositions, processes for preparing them and their use in the treatment of cytokine mediated diseases.
  • TNF Tumor necrosis factor
  • IL-1 interleukin-1
  • Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A.E., et al., 1995, J. Invest. Med. 43: 28-38).
  • cytokines may be involved in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al., 2001 Mar, Coron Artery Dis 12(2):107-13).
  • PTCA percutaneous transluminal coronary angioplasty
  • An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNF ⁇ ) and IL-l ⁇ .
  • TNF also referred to in its secreted cell-free form as TNF ⁇
  • IL-l ⁇ IL-l ⁇
  • Efficacy has been demonstrated with a monoclonal antibody directed against TNF ⁇ in a number of autoimmune diseases (Heath, P., "CDP571: An Engineered Human IgG4 Anti- TNF ⁇ Antibody” IBC Meeting on Cytokine Antagonists, Philadelphia, PA, April 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E.C.C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W.A., et al., 1997, Lancet 349: 521-524).
  • the monoclonal antibody is thought to function by binding to both soluble TNF ⁇ and to membrane bound TNF.
  • a soluble TNF ⁇ receptor has been engineered that interacts with TNF ⁇ . The approach is similar to that described above for the monoclonal antibodies directed against TNF ⁇ ; both agents bind to soluble TNF ⁇ , thus reducing its concentration.
  • Enbrel Immunex, Seattle, WA
  • Another version of the TNF ⁇ receptor, Ro 45-2081 has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury.
  • Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgGl gene and expressed in eukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).
  • IL-1 has been implicated as an immunological effector molecule in a large number of disease processes.
  • IL-1 receptor antagonist (IL-lra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Anakinra, Amgen). In a phase III human clinical trial IL-lra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage. IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints.
  • Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed Pharmacother. 51, 58).
  • Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling.
  • Cytokines such as IL-1 and
  • TNF are potent stimulators of NO production.
  • NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al., 1996, J Bone Miner Res. 11, 300).
  • the promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated through other effectors such as prostaglandins and thromboxanes.
  • LL-1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al., 1996, Proc Soc Exp Biol Med. 211, 24).
  • IL-lRa in combination with methotrexate, a well-known antirheumatic drug, or in combination with other strategies designed to block the effects of tumor necrosis factor (TNF)-alpha.
  • TNF tumor necrosis factor
  • Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX- 2) expression.
  • COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M.K. O'Banion et al., Proc. Natl. Acad. Sci.U.S.A, 1992, 89, 4888.)
  • inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
  • IBD active inflammatory bowel disease
  • a mucosal imbalance of intestinal IL-1 and IL-lra is present in patients with IBD. Insufficient production of endogenous IL-lra may contribute to the pathogenesis of IBD (Cominelli, et al., 1996, Aliment Pharmacol Ther. 10, 49).
  • Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. The structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-1 (Holden, et al., 1995, Med Hypotheses, 45, 559).
  • IL-1 A role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified.
  • HIV human immunodeficiency virus
  • IL-lra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54).
  • IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a dysregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).
  • TNF ⁇ and IL-l ⁇ are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure.
  • ARDS acute respiratory distress syndrome
  • TNF ⁇ and IL-6 levels have also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection, diabetes and cardiovascular disease.
  • TNF ⁇ expression Abnormalities in TNF ⁇ expression have been noted for each of the above conditions (Lommeda, et al., 1998, FASEB J. 12, 57). It has been proposed that elevated levels of TNF ⁇ are involved in other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). An inhibitor of TNF ⁇ production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al., 1997, J Neuroimmunol. 72, 169).
  • Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease.
  • cytokines such as IL-1 and TNF have been suggested to promote the disease.
  • an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al., 1998, Circulation, 97, 242).
  • TNF ⁇ levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M.A. Higham et al., 2000, Eur. Respiratory J., 15, 281). Circulating TNF ⁇ may also contribute to weight loss associated with this disease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179).
  • TNF ⁇ levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A.M. Feldman et al., 2000, J. Amer. College of Cardiology, 35, 537).
  • TNF ⁇ has been implicated in reperfusion injury in lung (Borjesson et al., 2000, Amer. J. Physiol., 278, L3- 12), kidney (Lemay et al., 2000, Transplantation, 69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844, 192).
  • TNF ⁇ is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al., 2000, J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNF ⁇ has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78, 1625).
  • iNOS inducible nitric oxide synthetase
  • IL-1 has also been shown to induce uveitis in rats which could be inhibited with LL-1 blockers.
  • Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65).
  • IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented by the administration of an anti- IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177).
  • cytokine Data obtained from LL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al., 1998, Clin Exp Pharmacol Physiol. 25, 141).
  • a variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813).
  • the production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.
  • LL-8 correlates with influx of neutiophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et al., 1996, Molecular Medicine Today 2, 482).
  • an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutiophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
  • neutiophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
  • Rhino virus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).
  • IL-8 diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.
  • IL-6 The proinflammatory cytokine IL-6 has been implicated with the acute phase response.
  • IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias (Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15: 307).
  • IL-6 also plays a significant role in osteoporosis. In murine models it has been shown to effect bone resorption and to induce osteoclast activity (Ershler et al., 1997, Development and Comparative Immunol. 21: 487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget's disease (Mills, et al., 1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer cachexia.
  • IL-6 and IFN alpha as key factors in both symptom formation and in host defense.
  • Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997, Protein Sci.
  • GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including burn- wound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs.
  • HIV human immunodeficiency virus
  • Involved cytokines include GM-CSF amongst others (Lee, 1998, J R Coll Physicians Lond 32, 56). Interferon ⁇ (IFN ⁇ ) has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft- versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFN ⁇ . These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173).
  • Type 1 insulin- dependent diabetes
  • LFN ⁇ LFN ⁇
  • TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to the development of lesions in the central nervous system for diseases such as multiple sclerosis (MS) and AIDS dementia complex (Martino et al., 1998, Ann Neurol. 43, 340).
  • Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral infarction.
  • Many activated immune cells are present in these lesions, mainly T-cells and macrophages.
  • cytokines such as TNF, IL-1 and IFN ⁇ . These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA specific for IFN ⁇ following challenge with Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342).
  • cytokines including IFN ⁇ has been shown to increase following a delayed type hypersensitivity reaction thus indicating a role for IFN ⁇ in atopic dermatitis (Szepietowski, et al., 1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologic studies were performed in cases of fatal cerebral malaria. Evidence for elevated IFN ⁇ amongst other cytokines was observed indicating a role in this disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501). The importance of free radical species in the pathogenesis of various infectious diseases has been established.
  • the nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as LFN ⁇ (Akaike, et al., 1998, Proc Soc Exp Biol Med. 217, 64).
  • cytokines such as LFN ⁇
  • Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma.
  • Viral gene expression and replication in HBV transgenic mice can be suppressed by a post-tianscriptional mechanism mediated by JFN ⁇ , TNF and IL-2 (Chisari, et al., 1995, Springer Semin Immunopathol. 17, 261).
  • LFN ⁇ can selectively inhibit cytokine induced bone resorption.
  • NO nitric oxide
  • NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilbourn, et al, 1997, Dis Mon. 43, 277).
  • IFN ⁇ is required for progression of chronic intestinal inflammation in such diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through the intermediacy of CD4+ lymphocytes probably of the TH1 phenotype (Sartor 1996,
  • WO 01/01986 discloses particular compounds alleged to having the ability to inhibit
  • TNF-alpha TNF-alpha.
  • the specific inhibitors disclosed are structurally distinct from the novel compounds disclosed in the present application disclosed hereinbelow.
  • Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic-neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotiophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS syndromes
  • FDA-approved disease- modifying antirheumatic drugs used in rheumatoid arthritis include hydroxychloroqume, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, cyclosporine, leflunomide, and the cytotoxic drugs methotrexate , azathioprine and cyclophosphamid. See also Lorenzen I., 1975 Jun., Annals of Clinical Research 7(3):195-201; and Currey HL., 1970 Transactions of the St Johns Hospital Dermatological Society 56(2): 117-21 More recently, biologic agents like etanercept, infliximab and anakinra have been approved by the FDA and on other major markets.
  • Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases including RA, and is responsible for the enhanced expression of many proinflammatory gene products.
  • the anti-inflammatory effect of Urtica extract (IDS23) is possibly attributed to its inhibitory effect on NF-kappaB activation.
  • IDS23 Urtica extract
  • Riehemann K. et al. 1999 Jan 8 FEBS Letters. 442(l):89-94. It is therefore expected that inhibition of NF- kappaB alone or in combination is a potential RA therapy of the future.
  • Small molecule inhibitors directed against enzymes involved in signal transduction pathways like NF- kappaB or to cell adhesion molecules like LFA-1 or ICAM-1 are also being developed as potential RA therapies.
  • angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline and thalidomide to treat rheumatoid arthritis has also been reported.
  • Yoo recommends formal studies to measure efficacy of thalidomide in rheumatoid arthritis, or with other compounds.
  • Yoo WH. et al. 2000 Jun., Journal of Rheumatology 27(6):1572-3.
  • Taxol see Arsenault AL., et al., 1998 Mar., Clinical Immunology & Immunopathology 86(3):280-9; Interferon beta-IB has also been studied as a possible treatment. Jabaily JA., et al. 1997 Jul., Arthritis & Rheumatism 40(7): 1370. Studies have also been done on the effect of alpha-interferon in RA. Shiozawa S. et al., 1992 Jun., British Journal of Rheumatology 31(6):405-8.
  • RA non-steroidal antiinflammatory drugs
  • glucocorticosteroids such as betamethasone, dexamethasone, deflazacort, methylprednisolone and prednisolone to treat rheumatoid arthritis (RA) is highly effective , even in patients who are receiving combination therapy with one or more DMARDs (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002 Feb., Arthritis & Rheumatism 46(2): 328-346).
  • DMARDs American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002 Feb., Arthritis & Rheumatism 46(2): 328-346.
  • Combination therapy comprising of one or more compounds classified as DMARDs together with an NSALD and/or steroid, is a common principle to treat RA at presence and will increasingly be the therapeutic paradigm of the future.
  • Treatment of psoriasis using cytostatic drugs has been reported by Griffiths CE. et al., 2000 Health Technology Assessment 4(40): 1-125; Dubertret L., 1998 Dec. Journal of Dermatology 25(12):788-92; Farber EM. et al., 1976 Nov 29 Archives of Dermatology. 112 Spec no: 1679-88.
  • calcipotriol and other antipsoriatic agent including: fluocinonide, tacalcitol, hydrocortisone, betamethasone, halobetasol (ulobetasol), ultraviolet B or psoralen ultraviolet A (PUNA) phototherapy, dithranol , maxacalcitol , acitretin, cyclosporine, were studied. Scott LJ. Et al., 2001 American Journal of Clinical Dermatology 2(2):95-120.
  • Calcitriol and tacalitol new retinoids such as the topical retinoid tazarotene, 4-hydroxylase- and 24-hydroxylase inhibitors, immunomodulatory treatments including tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T and LFA3TIP have been described as potential psoriasis treaments.
  • van De Kerkhof PC 2001 May- Jun., Skin Pharmacology & Applied Skin Physiology 14(3): 129-35. Methotrexate is also indicated to be effective. Chu T. 2000 Mai'., Practitioner 244(1608):238-42, 244.
  • Mometasone is a well tolerated topical glucocort coid effective in the management of patients with atopic dermatitis, seborrhoeic dermatitis, scalp psoriasis and psoriasis vulgaris. Prakash A. et al., 1998 Jan., Drugs 55(1).T 45-63. In the same review, the following actives were mentioned in comparison to mometasone: betamethasone, methylprednisolone, clobetasone, hydrocortisone, ketoconazole, fluocinolone acetonide, fluticasone, triamcinolone acetonide and diflucortolone. Holick et al.
  • PTKs Protein tyrosine kinases
  • EGFR epidermal growth factor receptor
  • PTK inhibitors including 4-(3- bromophenylamino)-6,7-dimethoxyquinazoline AG-1571 (SU-5271) by SUGEN Inc and including 4-(3-chorophenylamino)-6,7-dimethoxyquinazoline may therefore be useful in the treatment of psoriasis.
  • PTKs may also have a role in numerous other diseases including cancer, leukemia and restenosis. Ben-Bassat H. et al., 2000 Jun., Current Pharmaceutical Design 6(9):933-42.
  • Orfanos reports that oral retinoids for use in treating pustular and erythrodermic variants and plaque-type psoriasis may act synergistically with many other topical antipsoriatic agents (corticosteroids, anthralin, tar, and phototherapies). Orfanos CE., 1999 Nov., Cutis 64(5):347-53; see also Saurat JH., 1999 Sep., Journal of the American Academy of Dermatology 41(3 Pt 2):S2-6.
  • DMF dimethylfumarate
  • An inhibitory effect on cytokine-induced endothelial adhesion molecule expression has been found and indicates that dimethylfumarate may be useful in treating in psoriasis.
  • compositions comprising p38 kinase inhibitors in combination with one or more other active ingredients described herein.
  • a beneficial therapeutic effect is desirable in the treatment of cytokine mediated diseases, particularly in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, if one or more, preferably one of the active ingredients (hereafter referred to as A) described herein is or are used together with one or more, preferably one, p38 kinase inhibitor (hereafter referred to as B).
  • An additive or over-additive effect of the pharmaceutical combinations according to the invention provides for dose reduction side- effect reduction and/or interval extension when compared to the individual compounds of and A and B used in monotherapy in the usual way.
  • non-steroid anti- inflammatory drugs which are widely used for the treatment of inflammation, pain and fever.
  • These include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tiomethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprof
  • active ingredient A are immunosuppressive, immunomodulatory, or cytostatic drugs including hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate , azathioprine and cyclophosphamide.
  • immunosuppressive, immunomodulatory, or cytostatic drugs including hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate , azathioprine and cyclophosphamide.
  • active ingredient A are angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline and thalidomide,
  • Biological agents shall be understood to mean any natural or artificial/synthetic biological molecule or fragment thereof as known in the art, such as antibodies, proteins, fusion proteins, receptors, nucleic acids, lipids, carbohydrates and the like. Therefore, also within the scope of the invention for active ingredient A are biological agents, such as etanercept, infliximab, adalimumab, CDP 571, Ro 45-2081 (Lenercept), anakinra, alpha-interferon, interferon beta 1-B and other antibodies or receptor constructs directed against TNF-alpha, LL-l-RA, 11-6, LFA-1, CTLA 4Ig, and C5.
  • biological agents such as etanercept, infliximab, adalimumab, CDP 571, Ro 45-2081 (Lenercept), anakinra, alpha-interferon, interferon beta 1-B and other antibodies or receptor constructs directed against TNF-alpha, LL-l-RA, 11
  • active ingredient A are steroids and vitamin D3 analogs, alone (the latter being used mostly for psoriasis ) or in combination.
  • Steroids include fluocinonide, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, clobetasone, deflazacort, fluocinolone acetonide, fluticasone, triamcinolone acetonide Mometasone and diflucortolone.
  • Vit D derivatives are calcipotriol tacalcitol maxacalcitol and tacalitol, the calciotiopic homiones l,25(OH)2D3 and parathyroid hormone-related peptide.
  • active ingredient A is many types of immunomodulatory treatments or cytostatic drags including cyclosporin, tacrolimus, ascomycine, mycophenolate mofetil, hydroxyurea, 6-thioguanine methotrexate cyclophosphamide (Orfanos CE., 1999 Nov., Cutis 64(5):347-53); alefacept, leflunomide, infliximab, etanercept, nti-CD4, anti-CD25, peptide T, LFA3TIP, DAB389 (Gott Kunststoff et al, 1995), CTLA-4Ig (Lebwohl et al, 1997), anti-CD80 for example DEC-114 or ABX-IL8, anti-TAC, and daclizumab.
  • immunomodulatory treatments or cytostatic drags including cyclosporin, tacrolimus, ascomycine, mycophenolate mofetil, hydroxyurea, 6-thioguanine methotrexate cyclophos
  • PTKs protein tyrosine kinases
  • EGFR epidermal growth factor receptor
  • E-selectin inhibitors and widely used for psoriasis anthralin, tar, phototherapies including ultraviolet B (UVB) or psoralen ultraviolet A (PUVA), photodynamic therapy and laser therapy.
  • UVB ultraviolet B
  • PUVA psoralen ultraviolet A
  • retinoids therapy for example bexarotene, acitretin, etretinate and tazarotene, and hydroxyurea, 6-thioguanine and phototherapies.
  • Orfanos CE. 1999 Nov., Cutis 64(5):347-53; see also Saurat JH., 1999 Sep., Journal of the American Academy of Dermatology 41(3 Pt 2):S2-6.
  • small molecule inhibitors directed against enzymes involved in signal transduction pathways or to cell adhesion molecules like LFA-1 or ICAM-1.
  • the p38 kinase inhibitors within the scope of the present invention are compounds chosen from those disclosed in US Patents 6,319,921, 6,358,945, 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, and US 5,716,955; and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876,
  • compositions according to the invention are those p38 inhibitors disclosed in 6,319,921, 6,358,945, US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO
  • the invention relates to pharmaceutical combinations comprising A and p38 kinase inhibitor B chosen from the compounds of formula disclosed in WO 00/43384 and corresponding US patent 6,319,921:
  • Ar 1 is a heterocyclic group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and wherein Aii may be substituted by one or more R l5 R or R 3 ;
  • Ar 2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R 2 groups;
  • L a linking group
  • phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, C 1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, hydroxy, cyano, C 1- alkyloxy which is optionally partially or fully halogen
  • R 3 is selected from the group consisting of: a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein such phenyl, naphthy
  • cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C 1-3 alkyl groups; and e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; f) C 1-6 branched or unbranched alkyl which may optionally be partially or fully halogenated;
  • R t and R 2 taken together may optionally form a fused phenyl or pyridinyl ring,
  • each Rs, R B is independently selected from the group consisting of: hydrogen and C 1-4 branched or unbranched alkyl which may optionally be partially or fully halogenated;
  • each t , R 5 , Re, R 7 , R 9 , R 10 , R ⁇ and R 12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole;
  • X O or S and physiologically acceptable acids or salts thereof.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl.
  • a more preferred subgeneric aspect of the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein Ar 2 is naphthyl.
  • a yet more preferred subgeneric aspect of the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein: Ai ⁇ is thiophene or pyrazole; Ar 2 is 1 -naphthyl;
  • L is C 1-6 saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C 1- branched or unbranched alkyl which may be substituted by one or more halogen atoms;
  • Ri is selected from the group consisting of C 1-4 alkyl branched or unbranched, cyclopropyl and cyclohexyl which may optionally be partially or fully halogenated and which may optionally be substituted with one to three C 1- alkyl groups;
  • R 3 is selected from the group consisting of C 3-10 alkyl branched or unbranched, cyclopropanyl, cyclopentanyl, phenyl, pyridinyl each being optionally substituted as described above and alkoxycarbonylalkyl.
  • a yet further preferred subgeneric aspect of the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein Ari is pyrazole.
  • a still yet further preferred subgeneric aspect of previous the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein L is C 1-5 saturated carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C branched or unbranched alkyl which may be substituted by one or more halogen atoms.
  • L is propoxy, ethoxy, methoxy, methyl, propyl, C 3-5 acetylene or methylamino each being optionally substituted are described herein.
  • a more particularly preferred embodiment of L is ethoxy optionally substituted.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds:
  • Particularly preferred p38 kinase inhibitors B within the scope of the present invention are the following compounds:
  • the invention relates pharmaceutical combinations comprising compounds A and B, wherein the p38 kinase inhibitor B is selected from the compounds of the formula disclosed in WO 00/55139 and corresponding US patent no. 6,358,945:
  • Ari is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene;
  • Art may be substituted by one or more Ri, R or R 3 ;
  • Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three R groups;
  • X is: a) a C 5-8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C 1- branched or unbranched alkyl, C 1-4 alkoxy or C 1-4 alkylamino chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 0-3 C 1-4 branched or unbranched alkyl, C 1-4 alkoxy, hydroxy, nitrile, mono- or di-(C ⁇ -3 alkyl)amino, C 1-6 alkyl-S(O) m , or halogen;
  • Y is: a bond or a C 1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O) or S and wherein Y is optionally independently substituted with 0-2 oxo groups and one or more C 1-4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
  • C ⁇ - 6 branched or unbranched alkyl which is optionally partially or fully halogenated, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, hydroxy, nitrile, C 1-3 alkyloxy which is optionally partially or fully halogenated, NH 2 C(O) and di(C 1 _ 3 )alkylaminocarbonyl;
  • R 3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofurany
  • Ri and R 2 taken together may optionally form a fused phenyl or pyridinyl ring;
  • each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C 1-4 branched or unbranched alkyl optionally be partially or fully halogenated;
  • each R t , R 5 , R ⁇ , R 7 , R 9 , R 10 , R ⁇ and R 12 is independently selected from the group consisting of mo ⁇ holine, piperidine, piperazine, imidazole and tetrazole;
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Ari is selected from thiophene and pyrazole;
  • X is C 5-7 cycloalkyl or C 5-7 cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 CM branched or unbranched alkyl, C 1- alkoxy or C 1-4 alkylamino; or
  • X is phenyl, pyridine, tetrahydropyridine, pyrimidine, furan or thiophene each being optionally independently substituted with 0-3 C 1-4 branched or unbranched alkyl, C 1-4 alkoxy, hydroxy, nitrile, mono- or di-(C 1-3 alkyl)amino, C 1-6 alkyl- S(O) m or halogen;
  • Ri is C 1-4 alkyl branched or unbranched, cyclopropyl or cyclohexyl optionally partially or fully halogenated and optionally substituted with one to three C 1- alkyl groups;
  • R 3 is C 1-4 alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl or pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substitute
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: is pyrazole;
  • X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with an oxo group or 0-3 C 1-4 branched or unbranched alkyl, C 1-4 alkoxy or C 1-4 alkylamino; or X is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 0-3 C 1-4 branched or unbranched alkyl, C 1-4 alkoxy, hydroxy, nitrile, mono- or di-(C 1-3 alkyl)amino, C 1-6 alkyl-S(O) m or halogen.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
  • Y is -CH2-, -CH2CH2-, -CH2NH-, -CH2CH2NH- or a bond; and Z is phenyl, imidazole, furan, piperazine, tetrahydropyran, mo ⁇ holine, thiomo ⁇ holine, thiomo ⁇ holine sulfoxide, piperidine, pyridine, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C 1-3 alkyl and C 1-5 alkoxyalkyl, phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkoxy, hydroxy or mono- or di-(C 1-3 alkyl)amino, C 1-6 alkyl-S(O) m and phenyl-S(O) m wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkoxy
  • p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted by R 3 ;
  • R 3 is C 1-4 alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl, pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein X is pyridinyl.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein the pyridinyl is attached to A ⁇ via the 3-pyridinyl position.
  • pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein particular compounds are chosen from:
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds:
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds of the formula described in WO 00/55139 and corresponding US patent no. 6,358,945:
  • Ar! is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene;
  • Ari is optionally substituted by one or more R 1 ⁇ R 2 or R 3 ;
  • Ar 2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole each being optionally substituted with zero to three R groups;
  • X is: a C 5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C 1-4 alkyl, C 1- alkoxy or C ⁇ -4 alkylamino chains each being branched or unbranched;
  • Z is: aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetiazolyl, furanyl, thienyl and pyranyl, heterocycle selected from piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl,
  • R 2 is: a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile, or R is acetyl, aroyl, C 1-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl;
  • R 3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetiahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is
  • cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bi cycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C 1- alkyl groups; d) C5- cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohex
  • R ⁇ and R 2 taken together optionally form a fused phenyl or pyridinyl ring;
  • each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C branched or unbranched alkyl optionally partially or fully halogenated;
  • each R t , R 5 , Re, R 7 , R 9 , R ⁇ ⁇ ! R ⁇ and R 12 is independently selected from the group consisting of mo ⁇ holine, piperidine, piperazine, imidazole and tetrazole;
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Ar 2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Aii is thiophene or pyrazole each substituted independently by one to three Ri, R 2 or
  • X is: a C 5- cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C M alkyl, C 1-4 alkoxy or C M alkylamino chains each being branched or unbranched;
  • phenyl indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl, tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperdinyl, benzimidazole or piperazinyl; each being optionally independently substituted with one to three C 1-4 alkyl, C 1-4 alkoxy, hydroxy, nitrile, amino, mono- or di-(C 1- alkyl)amino, mono- or di-(C ⁇ _ 3 alkylamino)carbonyl, NH 2 C(O), C 1-6 alkyl-S(O) m or halogen;
  • Y is: a bond or a C 1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O or N, and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C alkyl optionally substituted by one or more halogen atoms;
  • Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl and thienyl, heterocycle selected from piperazinyl, 2-oxa-5-aza-bicyclo[2.2.1Jheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, mo ⁇ holino, thiomo ⁇ holino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkoxy-C 1-3 alkyl, C 1-6 alkoxycarbonyl, aroyl, mo ⁇ holinocarbonyl, C 1- acyl, oxo, hydroxy, pyridinyl-C ⁇ -3 alkyl, imidazolyl-C 1-3 alkyl, tetrahydr
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally partially or fully halogenated and optionally substituted with one to three C 1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH;
  • nitrile is: a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
  • phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C 1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl d_5 alkyl, naphthyl C 1-5 alkyl, halogen, hydroxy, oxo, nitrile, C 1-3 alkoxy optionally be partially or fully halogenated, C 1-3 alkoxyC
  • heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1-3 )alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH C(O), a mono- or di-(C 1-3 )alkyl aminocarbonyl, C 1 .
  • a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl; wherein the fused aryl is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C 1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C 1-3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyl oxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this
  • cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C ⁇ -3 alkyl groups;
  • R t and R 2 taken together optionally form a fused phenyl or pyridinyl ring;
  • each R 8 and R 13 is independently selected from the group consisting of: hydrogen and C 1-4 branched or unbranched alkyl optionally partially or fully halogenated; and each , R 5 , R 6 , R 7 , R 9 , R 10> R ⁇ and R 12 is independently selected from the group consisting of mo ⁇ holine, piperidine, piperazine, imidazole and tetrazole;
  • p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: An is pyrazole;
  • X is: cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted with an oxo group or one to three C ⁇ -4 alkyl, C 1-4 alkoxy or C 1-4 alkylamino chains each being branched or unbranched;
  • phenyl, furanyl, thienyl, pyridinyl, pyrazinyl piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C 1-2 alkyl, C 1-2 alkoxy, hydroxy or halogen;
  • phenyl is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1Jheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydiOpyranyl, piperazinyl, mo ⁇ holino, thiomo ⁇ holino, thiomo ⁇ holino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-3 alkoxy-d- 3 alkyl, C 1-6 alkoxycarbonyl, aroyl, mo ⁇ holinocarbonyl, C ⁇ -3 acyl, oxo, hydroxy, pyridinyl
  • cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl optionally partially or fully halogenated and optionally substituted with one to three d- 3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH; C 3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C 1-3 branched or unbranched alkyl;
  • R 2 is: a C ⁇ - 6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
  • R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C ⁇ -6 branched or unbranched alkyl which is optionally partially or fully halogenated, phenyl d.
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three d- 3 alkyl groups
  • R taken together optionally form a fused phenyl or pyridinyl ring.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
  • Y is -CH 2 -, -O-(CH 2 )o -3 -, -CH 2 CH 2 -, -CH 2 NH-, -CH 2 CH 2 -NH-, NH-CH 2 CH 2 -, -CH 2 -NH-CH 2 -, -NH-, -NH-C(O)-, -C(O)-, -CH(OH)-, -CH 2 (CH 2 CH 3 )- or a bond;
  • X is: cyclohexenyl optionally substituted with an oxo group or one to three C 1-4 alkyl, C M alkoxy or C M alkylamino chains each being branched or unbranched;
  • phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C ⁇ _ 2 alkyl, C 1-2 alkoxy, hydroxy or halogen;
  • Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2. ljheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, mo ⁇ holino, thiomo ⁇ holino, thiomo ⁇ holino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, d-6 alkyl, C 1-6 alkoxy, d-3 alkoxy-d.3 alkyl, C 1-6 alkoxycarbonyl, aroyl, mo ⁇ holinocarbonyl, d ⁇ acyl, oxo, hydroxy, pyridinyl-C ⁇ _ 3 al
  • C 1-6 alkoxy; or Z is hydroxy, hydroxyd.3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C ⁇ - 3 alkyl, pyridinylC 1-2 alkyl, tetrahydrafuranylC 1- alkyl, Cj.3 alkoxyd- 3 alkyl, C 1-3 acyl, nitrileC 1- alkyl, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C 1-6 alkoxy, hydroxy or mono- or di-(C 1-3 alkyl)amino, or Z is C 1-6 alkyl branched or unbranched, C 1-6 alkoxy or nitrileC 1-4 alkyl;
  • Ri is:
  • R 2 is: a d- 3 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
  • R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of C ⁇ -3 branched or unbranched alkyl which is optionally partially or fully halogenated, d-3 alkoxy which optionally partially or fully halogenated, d. 3thioalkyl, d-sthioalkyld-salkyl, amino or NH 2 C(O);
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three -3 alkyl groups.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
  • Z is: phenyl, heteroaryl selected from pyridinyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1Jheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl, mo ⁇ holino, thiomo ⁇ holino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three d-3 alkyl, C 1-3 alkoxy, oxo , hydroxy or NH 2 C(O)-; or Z is hydroxyC 1-3 alkyl, amino wherein the N atom is optionally independently mono- or di-substituted by pyridinylmethyl, tetrahydrafuranylmethyl, C 1-3 alkoxyd- 3 alkyl, C 1-3 acyl or nitrileC 1-4 alkyl, or Z is nitrileC 1- alky
  • R 3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to two groups selected from the group consisting of C 1-2 alkyl which is optionally partially or fully halogenated, C 1-2 alkoxy which optionally partially or fully halogenated, C 1-2 thioalkyl, C 1-2 thioalkylC 1-3 alkyl, amino or NH 2 C(O);
  • R 3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C 1-3 alkyl groups.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein X is pyridinyl.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein the pyridinyl is attached to A ⁇ via the 3- pyridinyl position.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from:
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds of formula as disclosed in WO 00/55139 and corresponding US patent no. 6,358,945:
  • G is : an aromatic C 6 - 10 carbocycle or a nonaromatic C . 10 carbocycle saturated or unsaturated; a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from O, N and S; a 5-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; or an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S; wherein G is substituted by one or more R ls R 2 or R 3 ;
  • Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more f or R 5 ;
  • X is: a C 5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three CM alkyl, CM alkoxy or C 1-4 alkylamino chains;
  • phenyl furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl;
  • Y is: a bond or a CM saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C 1-4 alkyl optionally substituted by one or more halogen atoms;
  • Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetiazolyl, furanyl, thienyl, pyranyl each being optionally substituted with one to three halogen, Cj- 6 alkyl, C 1-6 alkoxy, hydroxy, amino, mono- or di- (d.
  • each Rt is independently:
  • C 1-10 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C 3 . 10 cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C 1-6 alkyl which is optionally partially or fully halogenated, d-s cycloalkanyl, C 5 .8 cycloalkenyl, hydroxy, nitrile, d-3 alkoxy which is optionally partially or fully halogenated or NH C(O), mono- or di(C ⁇ -3 alkyl)amino, and mono- or di(C ⁇ -3alkyl)amino
  • phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C 1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC 1-3 alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
  • C 3-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally be substituted with one to three d -5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with zero to five halogen, C 1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, d -3 alkyloxy which is optionally partially or fully hal
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three d-3 alkyl groups;
  • each R 2 , Rt, and R 5 is a C 1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C 1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, nitrile, methoxycarbonyl, C 1-3 alkyl-S(O) m optionally partially or fully halogenated, or phenylsulfonyl;
  • each R 3 is independently: phenyl, naphthyl, mo ⁇ holinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, tetiazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purin
  • cyclopentenyl cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three C M alkyl groups; C alkyl-phenyl-C(O)-C 1-4 alkyl-, C 1-4 alkyl-C(O)-C 1-4 alkyl- or C 1-4 alkyl- phenyl-S(O) m -C 1-4 alkyl-;
  • R 20 C(O)N(R 21 >, R 22 O- or R 23 R 24 NC(O)-;
  • R 26 (CH 2 ) m C(O)N(R 21 )- or R 26 C(O)(CH 2 ) m N(R 21 )-;
  • R 6 is a:
  • each R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R ⁇ , R 19 , R 25 and R 26 is independently: nitrile, phenyl, mo ⁇ holino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetiazolyl, amino or mono- or di-(C 1- alkyl)amino optionally partially or fully halogenated;
  • each R ⁇ andR 16 is independently: hydrogen or C 1- alkyl optionally partially or fully halogenated;
  • R 18 is independently: hydrogen or a C M alkyl optionally independently substituted with oxo or R 25 ;
  • R 20 is independently:
  • Ci-io alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
  • R 21 is independently: hydrogen or C 1.3 alkyl optionally partially or fully halogenated
  • each R 22 , R 23 and R is independently: hydrogen, C 1-6 alkyl optionally partially or fully halogenated, said C 1-6 alkyl is optionally interrupted by one or more O, N or S, said C 1- alkyl also being independently optionally substituted by mono- or phenyl, pyridinyl, amino or mono- or di-(C 1-4 alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C 1- 3alkyl)amino; or R 2 3 and R 4 taken together optionally form a heterocyclic or heteroaryl ring;
  • n 0, 1 or 2;
  • W is O or S and pharmaceutically acceptable derivatives thereof.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein
  • G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the ⁇ 38 kinase inhibitor B is selected from the compounds immediately described above and wherein
  • G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more R l5 R 2 or R 3 ;
  • Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more t or R 5 groups;
  • X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl
  • Y is: a bond or a C saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(O) m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C M alkyl optionally substituted by one or more halogen atoms;
  • Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C 1-3 alkyl, C 1-3 alkoxy, amino, mono- or di-(C 1- alkyl)amino, CONH 2 or OH;
  • tetrahydropyranyl tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4- dioxanyl, mo ⁇ holinyl, thiomo ⁇ holinyl, thiomo ⁇ holino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetiahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C M alkyl, C M alkoxy, amino, mono- or di-
  • each Rt is independently:
  • C 3-6 alkyl optionally partially or fully halogenated, and optionally substituted with one to three C 3-6 cycloalkyl, phenyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to three groups selected from halogen, C 1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or d ⁇ alkoxy which is optionally partially or fully halogenated;
  • R 2 is independently: halogen, C 1-3 alkoxy, C 1 - 3 alkyl-S(O) m optionally partially or fully halogenated, phenylsulfonyl or nitrile;
  • R 3 is independently: phenyl, mo ⁇ holino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolylidinyl, imidazolyl, pyrazolyl, each being optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, d.
  • alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C 1-5 alkyl, naphthyl C 1-5 alkyl, halogen, oxo, hydroxy, nitrile, d- 3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C 1-3 alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH 2 C(O),
  • OR 18 or d.6 alkyl optionally substituted with OR 18 ;
  • R 20 C(O)N(R 21 )-, R 22 O- ; R 23 R 2 NC(O)-; R 26 CH 2 C(O)N(R 21 )- or
  • R 26 C(O)CH 2 N(R 21 )-; C 2- alkenyl substituted by R 2 3R 4 NC(O)-; or
  • C 2- alkynyl branched or unbranched carbon chain optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, mo ⁇ holinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetiazolyl or one or more C 1-4 alkyl optionally substituted by one or more halogen atoms; and
  • R 23 and R 24 taken together optionally form imidazolyl, piperidinyl, mo ⁇ holinyl, piperazinyl or a pyridinyl ring.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
  • G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more Ri, R 2 or R 3 ;
  • Ar is naphthyl
  • X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C 1-4 alkyl, C 1- alkoxy, hydroxy, nitrile, amino, mono- or di-(C 1-3 alkyl)amino, mono- or di-(d-3 alkylamino)carbonyl, NH 2 C(O), Cj -6 alkyl-S(O) m or halogen;
  • Y is: a bond or a C 1- saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group;
  • Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinyl which are optionally substituted with one to two C 1-2 alkyl or C 1-2 alkoxy; tetrahydropyranyl, mo ⁇ holinyl, thiomo ⁇ holinyl, thiomo ⁇ holino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetiahydropyrimidonyl which are optionally substituted with one to two C 1-2 alkyl or C 1-2 alkoxy; or
  • each R 1 is independently: d- 5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl substituted with zero to three halogen, d- 3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or which is optionally partially or fully halogenated;
  • cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl each being optionally partially or fully halogenated and optionally substituted with one to three d- 3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC 1-3 alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O; and
  • each R 2 is independently: bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile;
  • each R 3 is independently: phenyl, mo ⁇ holino, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, pyrazolyl, each of the aforementioned is optionally substituted with one to three d- 3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C alkyloxy optionally partially or fully halogenated;
  • Ci_ 3 alkyl or d -3 alkoxy each being optionally partially or fully halogenated or optionally substituted with R 17 ;
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein
  • G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one or more R ls R 2 or R 3 ;
  • Ar is 1 -naphthyl
  • X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
  • Y is: a bond or
  • each R ⁇ is independently:
  • each R 3 is independently: phenyl, mo ⁇ holinyl, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl or pyrazolyl, wherein any of the aforementioned is optionally substituted with C 1-2 alkyl which is optionally partially or fully halogenated;
  • C M alkyl or C alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino
  • R 23 and R 2 are H or R 23 and R 24 taken together optionally form mo ⁇ holino; and R 26 is mo ⁇ holino.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein G is phenyl, pyridinyl or naphthyl wherein G is substituted by one or more Ri, R 2 or R 3 ;
  • X is: imidazolyl or pyridinyl; Y is:
  • each Ri is independently: tert-butyl, sec-butyl, tert-amyl or phenyl;
  • R 2 is chloro
  • R 3 is independently: methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, mo ⁇ holino or mo ⁇ holinocarbonyl.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein X is pyridinyl.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein the pyridinyl is attached to Ar via the 3 -pyridinyl position.
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
  • Furan-2-carboxylic acid (4-tert-butyl-2- ⁇ 3-[4-(6-mo ⁇ holin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -ureido ⁇ -phenyl)-amide;
  • the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds :

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Abstract

The present invention relates to pharmaceutical combination therapies based on p38 kinase inhibitors and another active ingredient, pharmaceutical compositions comprising such combinations, processes for preparing them and their use in the treatment of cytokine mediated diseases.

Description

Combination Therapy with p38 MAP Kinase Inhibitors and their Pharmaceutical Compositions
APPLICATION DATA
This application claims benefit to US provisional application no.60/403,115 filed 8/13/2002.
TECHNICAL FIELD OF THE INVENTION
The present invention relates to p38 kinase inhibitors in combination with other active ingredients, their pharmaceutical compositions, processes for preparing them and their use in the treatment of cytokine mediated diseases.
BACKGROUND OF THE INVENTION
Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological entities collectively referred to as proinflammatory cytokines. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.
Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al., 1984, Rev. Infect. Disease 6:51). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A.E., et al., 1995, J. Invest. Med. 43: 28-38). Studies suggest that inflammatory changes mediated by cytokines may be involved in the pathogenesis of restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al., 2001 Mar, Coron Artery Dis 12(2):107-13). An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell-free form as TNFα) and IL-lβ. A number of anti-cytokine therapies are currently in clinical trials. Efficacy has been demonstrated with a monoclonal antibody directed against TNFα in a number of autoimmune diseases (Heath, P., "CDP571: An Engineered Human IgG4 Anti- TNFα Antibody" IBC Meeting on Cytokine Antagonists, Philadelphia, PA, April 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E.C.C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W.A., et al., 1997, Lancet 349: 521-524). The monoclonal antibody is thought to function by binding to both soluble TNFα and to membrane bound TNF.
A soluble TNFα receptor has been engineered that interacts with TNFα. The approach is similar to that described above for the monoclonal antibodies directed against TNFα; both agents bind to soluble TNFα, thus reducing its concentration. One version of this construct, called Enbrel (Immunex, Seattle, WA) recently demonstrated efficacy in a Phase III clinical trial for the treatment of rheumatoid arthritis (Brower et al., 1997, Nature Biotechnology 15: 1240). Another version of the TNFα receptor, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, NJ) has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury. Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgGl gene and expressed in eukaryotic cells (Renzetti, et al., 1997, Inflamm. Res. 46: S143).
IL-1 has been implicated as an immunological effector molecule in a large number of disease processes. IL-1 receptor antagonist (IL-lra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Anakinra, Amgen). In a phase III human clinical trial IL-lra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage. IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints. Antagonists of IL-1 have been shown to diminish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed Pharmacother. 51, 58). Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling. Cytokines such as IL-1 and
TNF are potent stimulators of NO production. NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al., 1996, J Bone Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1. Some of this damage may be mediated through other effectors such as prostaglandins and thromboxanes. LL-1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al., 1996, Proc Soc Exp Biol Med. 211, 24). Recently, interesting results were obtained using IL-lRa in combination with methotrexate, a well-known antirheumatic drug, or in combination with other strategies designed to block the effects of tumor necrosis factor (TNF)-alpha. Gabay C, 2000 Jan., Expert Opinion on Investigational Drugs 9(1): 113-27. Anakinra (an IL-1 receptor antagonist from Amgen) is under investigation for treatment of a variety of inflammatory conditions, including psoriasis.
Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX- 2) expression. COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M.K. O'Banion et al., Proc. Natl. Acad. Sci.U.S.A, 1992, 89, 4888.) Accordingly, inhibitors of cytokines such as IL-1 would be expected to exhibit efficacy against those disorders currently treated with COX inhibitors such as the familiar NSAIDs. These disorders include acute and chronic pain as well as symptoms of inflammation and cardiovascular disease.
Elevation of several cytokines have been demonstrated during active inflammatory bowel disease (IBD). A mucosal imbalance of intestinal IL-1 and IL-lra is present in patients with IBD. Insufficient production of endogenous IL-lra may contribute to the pathogenesis of IBD (Cominelli, et al., 1996, Aliment Pharmacol Ther. 10, 49). Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. The structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-1 (Holden, et al., 1995, Med Hypotheses, 45, 559). A role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified. IL-lra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzer, et al., 1997, Clin Exp Immunol. 109, 54). IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a dysregulation of both IL-1 and TNF (Howells, 1995, Oral Dis. 1, 266).
Proinflammatory cytokines such as TNFα and IL-lβ are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure. In a study of patients presenting at a hospital with sepsis, a correlation was found between TNFα and IL-6 levels and septic complications (Terregino et al., 2000, Aim. Emerg. Med., 35, 26). TNFα has also been implicated in cachexia and muscle degradation, associated with HIV infection (Lahdiverta et al., 1988, Amer. J. Med., 85, 289). Obesity is associated with an increase incidence of infection, diabetes and cardiovascular disease. Abnormalities in TNFα expression have been noted for each of the above conditions (Loffreda, et al., 1998, FASEB J. 12, 57). It has been proposed that elevated levels of TNFα are involved in other eating related disorders such as anorexia and bulimia nervosa. Pathophysiological parallels are drawn between anorexia nervosa and cancer cachexia (Holden, et al., 1996, Med Hypotheses 47, 423). An inhibitor of TNFα production, HU-211, was shown to improve the outcome of closed brain injury in an experimental model (Shohami, et al., 1997, J Neuroimmunol. 72, 169). Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease. In an animal model an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al., 1998, Circulation, 97, 242). TNFα levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M.A. Higham et al., 2000, Eur. Respiratory J., 15, 281). Circulating TNFα may also contribute to weight loss associated with this disease (N. Takabatake et al., 2000, Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179). Elevated TNFα levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A.M. Feldman et al., 2000, J. Amer. College of Cardiology, 35, 537). In addition, TNFα has been implicated in reperfusion injury in lung (Borjesson et al., 2000, Amer. J. Physiol., 278, L3- 12), kidney (Lemay et al., 2000, Transplantation, 69, 959), and the nervous system (Mitsui et al., 1999, Brain Res., 844, 192).
TNFα is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al., 2000, J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al., 2000, Arthritis and Rheumatism, 41, 2165). TNFα has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al., 1998, Laboratory Investigation, 78, 1625).
The abnormal expression of inducible nitric oxide synthetase (iNOS) has been associated with hypertension in the spontaneously hypertensive rat (Chou et al., 1998, Hypertension, 31, 643). IL-1 has a role in the expression of iNOS and therefore may also have a role in the pathogenesis of hypertension (Singh et al., 1996, Amer. J. Hypertension, 9, 867).
IL-1 has also been shown to induce uveitis in rats which could be inhibited with LL-1 blockers. (Xuan et al., 1998, J. Ocular Pharmacol, and Ther., 14, 31). Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65). IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented by the administration of an anti- IL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al., 1996, Am J Contact Dermat. 7, 177). Data obtained from LL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al., 1998, Clin Exp Pharmacol Physiol. 25, 141). A variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin Nutr. 62, 813). The production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.
Other proinflammatory cytokines have been correlated with a variety of disease states. LL-8 correlates with influx of neutiophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et al., 1996, Molecular Medicine Today 2, 482). Therefore, an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutiophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
Rhino virus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al., 1998, Am J Rhinol. 12, 17).
Other diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.
The proinflammatory cytokine IL-6 has been implicated with the acute phase response. IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias (Treon, et al., 1998, Current Opinion in Hematology 5: 42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al., 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in osteoporosis. In murine models it has been shown to effect bone resorption and to induce osteoclast activity (Ershler et al., 1997, Development and Comparative Immunol. 21: 487). Marked cytokine differences, such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget's disease (Mills, et al., 1997, Calcif Tissue Int. 61, 16). A number of cytokines have been shown to be involved in cancer cachexia. The severity of key parameters of cachexia can be reduced by treatment with anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al., 1995, Cytokins Mol Ther. 1, 107). Several infectious diseases, such as influenza, indicate IL-6 and IFN alpha as key factors in both symptom formation and in host defense (Hayden, et al., 1998, J Clin Invest. 101, 643). Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al., 1997, Protein Sci. 6, 929). Compounds that interfered with the production of cytokines including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in mice (Scholz et al., 1998, J. Med. Chem., 41, 1050).
GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including burn- wound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al., 1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs. Involved cytokines include GM-CSF amongst others (Lee, 1998, J R Coll Physicians Lond 32, 56). Interferon γ (IFN γ) has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft- versus-host disease (Parkman, 1998, Curr Opin Hematol. 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFN γ. These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al., 1995, Leuk Lymphoma. 19, 173). The development of insulin- dependent diabetes (Type 1) can be correlated with the accumulation in pancreatic islet cells of T-cells producing IFN γ (Ablumunits, et al., 1998, J Autoimmun. 11, 73). LFN γ along with TNF, IL-2 and IL-6 lead to the activation of most peripheral T-cells prior to the development of lesions in the central nervous system for diseases such as multiple sclerosis (MS) and AIDS dementia complex (Martino et al., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions result in arterial disease that can lead to cardiac and cerebral infarction. Many activated immune cells are present in these lesions, mainly T-cells and macrophages. These cells produce large amounts of proinflammatory cytokines such as TNF, IL-1 and IFN γ. These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997, Heart Vessels Suppl 12, 76). Allergic subjects produce mRNA specific for IFN γ following challenge with Vespula venom (Bonay, et al., 1997, Clin Exp Immunol. 109, 342). The expression of a number of cytokines, including IFN γ has been shown to increase following a delayed type hypersensitivity reaction thus indicating a role for IFN γ in atopic dermatitis (Szepietowski, et al., 1997, Br J Dermatol. 137, 195). Histopathologic and immunohistologic studies were performed in cases of fatal cerebral malaria. Evidence for elevated IFN γ amongst other cytokines was observed indicating a role in this disease (Udomsangpetch et al., 1997, Am J Trop Med Hyg. 57, 501). The importance of free radical species in the pathogenesis of various infectious diseases has been established. The nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as LFN γ (Akaike, et al., 1998, Proc Soc Exp Biol Med. 217, 64). Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma. Viral gene expression and replication in HBV transgenic mice can be suppressed by a post-tianscriptional mechanism mediated by JFN γ, TNF and IL-2 (Chisari, et al., 1995, Springer Semin Immunopathol. 17, 261). LFN γ can selectively inhibit cytokine induced bone resorption. It appears to do this via the intermediacy of nitric oxide (NO) which is an important regulatory molecule in bone remodeling. NO may be involved as a mediator of bone disease for such diseases as: the rheumatoid arthritis, tumor associated osteolysis and postmenopausal osteoporosis (Evans, et al., 1996, J Bone Miner Res. 11, 300). Studies with gene deficient mice have demonstrated that the IL-12 dependent production of IFN γ is critical in the control of early parasitic growth. Although this process is independent of nitric oxide the control of chronic infection does appear to be NO dependent (Alexander et al., 1997, Philos Trans R Soc Lond B Biol Sci 352, 1355). NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilbourn, et al, 1997, Dis Mon. 43, 277). IFN γ is required for progression of chronic intestinal inflammation in such diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through the intermediacy of CD4+ lymphocytes probably of the TH1 phenotype (Sartor 1996,
Aliment Pharmacol Ther. 10 Suppl 2, 43). An elevated level of serum IgE is associated with various atopic diseases such as bronchial asthma and atopic dermatitis. The level of IFN γ was negatively correlated with serum IgE suggesting a role for IFN γ in atopic patients (Teramoto et al., 1998, Clin Exp Allergy 28, 74).
WO 01/01986 discloses particular compounds alleged to having the ability to inhibit
TNF-alpha. The specific inhibitors disclosed are structurally distinct from the novel compounds disclosed in the present application disclosed hereinbelow. Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic-neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotiophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke's encephalophathy, Rett syndrome, homocysteinuria, hyperprolinemia, hyperhomocysteinemia, nonketotic hyperglycinemia, hydroxybutyric aminoaciduria, sulfite oxidase deficiency, combined systems disease, lead encephalopathy, Tourett's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety and schizophrenia.
Compounds which modulate release of one or more of the aforementioned inflammatory cytokines can be useful in treating diseases associated with release of these cytokines. For example, US patent nos. 6,319,921 and 6,358,945 disclose compounds which are indicated to be useful in treating cytokine mediated diseases.
The successful use of immunosuppressive, immunomodulatory, or cytostatic drugs to treat various inflammatory diseases has been reported extensively. Additionally, a heterogeneous class of drugs from different therapeutic entities has been formed in the field of rheumatology. In a review by Ward several of these so called disease-modifying antirheumatic drugs (DMARD) or slow-acting antirheumatic drugs (SAARD) are indicated as being useful to modify or alter the rheumatoid arthritis disease process. Ward JR., 1988 Oct 14, American Journal of Medicine 85(4A):39-44. FDA-approved disease- modifying antirheumatic drugs used in rheumatoid arthritis include hydroxychloroqume, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, cyclosporine, leflunomide, and the cytotoxic drugs methotrexate , azathioprine and cyclophosphamid. See also Lorenzen I., 1975 Jun., Annals of Clinical Research 7(3):195-201; and Currey HL., 1970 Transactions of the St Johns Hospital Dermatological Society 56(2): 117-21 More recently, biologic agents like etanercept, infliximab and anakinra have been approved by the FDA and on other major markets.
Activation of transcription factor NF-kappaB is elevated in several chronic inflammatory diseases including RA, and is responsible for the enhanced expression of many proinflammatory gene products. The anti-inflammatory effect of Urtica extract (IDS23) is possibly attributed to its inhibitory effect on NF-kappaB activation. Riehemann K. et al., 1999 Jan 8 FEBS Letters. 442(l):89-94. It is therefore expected that inhibition of NF- kappaB alone or in combination is a potential RA therapy of the future. Small molecule inhibitors directed against enzymes involved in signal transduction pathways like NF- kappaB or to cell adhesion molecules like LFA-1 or ICAM-1 are also being developed as potential RA therapies.
The use of angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline and thalidomide to treat rheumatoid arthritis has also been reported. Yoo recommends formal studies to measure efficacy of thalidomide in rheumatoid arthritis, or with other compounds. Yoo WH. et al., 2000 Jun., Journal of Rheumatology 27(6):1572-3. See also Keesal N., et al., 1999 Nov., Journal of Rheumatology 26(11):2344-7; Huizinga TW., et al., 1996 Nov., Annals of the Rheumatic Diseases 55(ll):833-6; Gutierrez-Rodriguez O. et al., 1989 Feb., Journal of Rheumatology 16(2):158-63; Miyachi Y. et al. 1985 Jul., Arthritis & Rheumatism 28(7):836; Gutierrez- Rodriguez O., 1984 Oct., Arthritis & Rheumatism. 27(10): 1118-21. Further regarding Taxol see Arsenault AL., et al., 1998 Mar., Clinical Immunology & Immunopathology 86(3):280-9; Interferon beta-IB has also been studied as a possible treatment. Jabaily JA., et al. 1997 Jul., Arthritis & Rheumatism 40(7): 1370. Studies have also been done on the effect of alpha-interferon in RA. Shiozawa S. et al., 1992 Jun., British Journal of Rheumatology 31(6):405-8. Other biologic agents, like antibodies against CTLA 4Ig (Moreland LW et al 2002, Arthritis & Rheumatism 46(6), 1470-1479), IL-6 (Choy et al 2001 Arthritis & Rheumatism 44 (9), S274), or C5 (Tesser J et al 2001, Arthritis & Rheumatism 44 (9), S274) have also been shown to demonstrate clinical efficacy in RA.
The use of the above mentioned drugs alone or in combination in RA has recently been reviewed by the American College of Rheumatology (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002 Feb., Arthritis & Rheumatism 46(2): 328-346). Combination therapy with two ore more DMARD was supported by the work of O 'Dell (O'Dell JR et. al., 1996., N Engl J Med 334: 1287-1291), who described increased, even over-additive efficacy and better tolerability for a combination of methotrexate, sulfasalazine, and hydroxychloroquine compared to the respective monotherapies alone. The concept of early aggressive therapy with several combination partners, followed by a stepwise removal of components is, therefore, increasingly popular (Pincus T., et.al., 1999, Ann Int Med 131: 768-774) and has replaced as the so-called "step-down" paradigm (Williams HJ et al. 1992, Arthritis Rheum 35:259-69) the previous "step-up" approach in RA therapy. The rationale for combination lies in the multi-factorial pathogenesis of the disease. The combination of compounds with different therapeutic targets is, therefore, able to increase the therapeutic response. Accumulating evidence on underlying mechnisms of disease and drug action, kowledge about genetic disposition of patients will result in a much more differentiated therapy in the future and boost the development of combination DMARD-therapies.
Another backbone of RA treatment is the use of non-steroidal antiinflammatory drugs (NSAID). Since they do not alter the course of the disease or prevent joint destruction, they should not be used as the sole treatment for RA (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002 Feb., Arthritis & Rheumatism 46(2): 328-346).
In addition, the use of glucocorticosteroids such as betamethasone, dexamethasone, deflazacort, methylprednisolone and prednisolone to treat rheumatoid arthritis (RA) is highly effective , even in patients who are receiving combination therapy with one or more DMARDs (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, 2002 Feb., Arthritis & Rheumatism 46(2): 328-346).
Combination therapy, comprising of one or more compounds classified as DMARDs together with an NSALD and/or steroid, is a common principle to treat RA at presence and will increasingly be the therapeutic paradigm of the future. Treatment of psoriasis using cytostatic drugs has been reported by Griffiths CE. et al., 2000 Health Technology Assessment 4(40): 1-125; Dubertret L., 1998 Dec. Journal of Dermatology 25(12):788-92; Farber EM. et al., 1976 Nov 29 Archives of Dermatology. 112 Spec no: 1679-88.
The use of steroids and vitamin D3 analogs, alone or in combination, to treat psoriasis has been described. For example, combination therapy with topical vitamin D analogues and steroids has been suggested for the treatment of psoriasis. Mason J. et al., 2002 Mar., British Journal of Dermatology 146(3):351-64. In comparative studies, calcipotriol and other antipsoriatic agent including: fluocinonide, tacalcitol, hydrocortisone, betamethasone, halobetasol (ulobetasol), ultraviolet B or psoralen ultraviolet A (PUNA) phototherapy, dithranol , maxacalcitol , acitretin, cyclosporine, were studied. Scott LJ. Et al., 2001 American Journal of Clinical Dermatology 2(2):95-120. Calcitriol and tacalitol, new retinoids such as the topical retinoid tazarotene, 4-hydroxylase- and 24-hydroxylase inhibitors, immunomodulatory treatments including tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T and LFA3TIP have been described as potential psoriasis treaments. van De Kerkhof PC, 2001 May- Jun., Skin Pharmacology & Applied Skin Physiology 14(3): 129-35. Methotrexate is also indicated to be effective. Chu T. 2000 Mai'., Practitioner 244(1608):238-42, 244. Mometasone is a well tolerated topical glucocort coid effective in the management of patients with atopic dermatitis, seborrhoeic dermatitis, scalp psoriasis and psoriasis vulgaris. Prakash A. et al., 1998 Jan., Drugs 55(1).T 45-63. In the same review, the following actives were mentioned in comparison to mometasone: betamethasone, methylprednisolone, clobetasone, hydrocortisone, ketoconazole, fluocinolone acetonide, fluticasone, triamcinolone acetonide and diflucortolone. Holick et al. conclude that the calciotiopic hormones l,25(OH)2D3 and parathyroid hormone-related peptide have wide-ranging clinical applications in dermatology. Holick MF, et al., 1996 Apr., Journal of Investigative Dermatology Symposium Proceedings 1(1): 1-9.
Protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (EGFR) have a role in inflammatory diseases, such as psoriaisis. PTK inhibitors including 4-(3- bromophenylamino)-6,7-dimethoxyquinazoline AG-1571 (SU-5271) by SUGEN Inc and including 4-(3-chorophenylamino)-6,7-dimethoxyquinazoline may therefore be useful in the treatment of psoriasis. Ben-Bassat H., 2001 Nov., Current Opinion in Investigational Drugs 2(11): 1539-45. PTKs may also have a role in numerous other diseases including cancer, leukemia and restenosis. Ben-Bassat H. et al., 2000 Jun., Current Pharmaceutical Design 6(9):933-42.
Treatment of psoriasis with retinoid therapy, for example the use of acitretin, etretinate and tazarotene has also been reported. Lebwohl et al. report that in addition to retinoids, methotrexate and cyclosporine are the only systemic drugs approved by the Food and Drug Administration for the treatment of psoriasis. Other drugs that are currently available include tacrolimus, mycophenolate mofetil, hydroxyurea, 6-thioguanine and sulfasalazine. Lebwohl M. et al., 2001 Nov., Journal of the American Academy of Dermatology 45(5):649-61; see also Kuenzli S. et al. 2001 May Current Opinion in hivestigational Drugs 2(5):625-30. Orfanos reports that oral retinoids for use in treating pustular and erythrodermic variants and plaque-type psoriasis may act synergistically with many other topical antipsoriatic agents (corticosteroids, anthralin, tar, and phototherapies). Orfanos CE., 1999 Nov., Cutis 64(5):347-53; see also Saurat JH., 1999 Sep., Journal of the American Academy of Dermatology 41(3 Pt 2):S2-6.
A proteasome inhibitor, PS-519, based upon the naturally occurring compound lactacystin, inhibits NF-kappa B activation and proved to be therapeutically effective in a SCπO-hu xenogeneic psoriasis transplantation model. Zollner TM. et al., 2002 Mar., Journal of Clinical Investigation 109(5): 671-9. It has been reported that dimethylfumarate (DMF) inhibits NF-kappaB activation. An inhibitory effect on cytokine-induced endothelial adhesion molecule expression has been found and indicates that dimethylfumarate may be useful in treating in psoriasis.
Treatment of Crohn's disease using a combination of small molecule inhibitors and groups of drugs including steroids/budesonide, 5-ASA drugs like mesalasine, immunosuppressants, biologies and adhesion molecule inhibitors would be effective. The work cited above supports the principle that p38 kinase inhibitors in combination with other active ingredients described hereinabove, would be effective treatment of rheumatoid arthritis, Crohn's diseases and psoriasis.
Summary of the Invention
In view of the work cited above there is a clear and increasing need for combination therapy administering compounds that inhibit p38 kinase in combination with one or more other active ingredients described herein inhibiting other targets, in a single pharmaceutical composition or administered individually, in order to treat various disease states.
It is another object of the invention to provide pharmaceutical compositions comprising p38 kinase inhibitors in combination with one or more other active ingredients described herein.
It is a further object of the invention to provide methods for treating diseases and pathological conditions involving inflammation such as rheumatoid arthritis, Crohn's diseases and psoriasis, using the pharmaceutical compositions of the invention.
Detailed Description of the Preferred Embodiments
A beneficial therapeutic effect, particularly an additive or over-additive effect or an overall reduction of side effects of therapy, is desirable in the treatment of cytokine mediated diseases, particularly in the treatment of rheumatoid arthritis, Crohn's disease and psoriasis, if one or more, preferably one of the active ingredients (hereafter referred to as A) described herein is or are used together with one or more, preferably one, p38 kinase inhibitor (hereafter referred to as B). An additive or over-additive effect of the pharmaceutical combinations according to the invention provides for dose reduction side- effect reduction and/or interval extension when compared to the individual compounds of and A and B used in monotherapy in the usual way. The effects mentioned above are observed both when the two active substances are administered simultaneously in a single active substance formulation and when they are administered successively in separate formulations. In the case of A being an injectable, especially a biological agent, other benefits of adding B may be seen. For example, cost reduction by way of interval and/or dose reduction.
Active Ingredient A:
Within the scope of the invention for active ingredient A are non-steroid anti- inflammatory drugs (NS AIDs) which are widely used for the treatment of inflammation, pain and fever. These include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, carprofen, indoprofen, ketorolac tiomethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like.
Also within the scope of the invention for active ingredient A are immunosuppressive, immunomodulatory, or cytostatic drugs including hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate , azathioprine and cyclophosphamide.
Also within the scope of the invention for active ingredient A are angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline and thalidomide,
Biological agents shall be understood to mean any natural or artificial/synthetic biological molecule or fragment thereof as known in the art, such as antibodies, proteins, fusion proteins, receptors, nucleic acids, lipids, carbohydrates and the like. Therefore, also within the scope of the invention for active ingredient A are biological agents, such as etanercept, infliximab, adalimumab, CDP 571, Ro 45-2081 (Lenercept), anakinra, alpha-interferon, interferon beta 1-B and other antibodies or receptor constructs directed against TNF-alpha, LL-l-RA, 11-6, LFA-1, CTLA 4Ig, and C5.
Also within the scope of the invention for active ingredient A are steroids and vitamin D3 analogs, alone (the latter being used mostly for psoriasis ) or in combination. Steroids include fluocinonide, hydrocortisone, betamethasone, halobetasol (ulobetasol), methylprednisolone, prednisolone, clobetasone, deflazacort, fluocinolone acetonide, fluticasone, triamcinolone acetonide Mometasone and diflucortolone. Among Vit D derivatives are calcipotriol tacalcitol maxacalcitol and tacalitol, the calciotiopic homiones l,25(OH)2D3 and parathyroid hormone-related peptide.
Also within the scope of the invention for active ingredient A are many types of immunomodulatory treatments or cytostatic drags including cyclosporin, tacrolimus, ascomycine, mycophenolate mofetil, hydroxyurea, 6-thioguanine methotrexate cyclophosphamide (Orfanos CE., 1999 Nov., Cutis 64(5):347-53); alefacept, leflunomide, infliximab, etanercept, nti-CD4, anti-CD25, peptide T, LFA3TIP, DAB389 (Gottlieb et al, 1995), CTLA-4Ig (Lebwohl et al, 1997), anti-CD80 for example DEC-114 or ABX-IL8, anti-TAC, and daclizumab. There are other targets or immune mediated products such as inhibitors of protein tyrosine kinases (PTKs) such as epidermal growth factor receptor (EGFR), E-selectin inhibitors, and widely used for psoriasis anthralin, tar, phototherapies including ultraviolet B (UVB) or psoralen ultraviolet A (PUVA), photodynamic therapy and laser therapy.
Also within the scope of the invention for active ingredient A are retinoids therapy, for example bexarotene, acitretin, etretinate and tazarotene, and hydroxyurea, 6-thioguanine and phototherapies. Orfanos CE., 1999 Nov., Cutis 64(5):347-53; see also Saurat JH., 1999 Sep., Journal of the American Academy of Dermatology 41(3 Pt 2):S2-6. Also within the scope of the invention for active ingredient A are small molecule inhibitors directed against enzymes involved in signal transduction pathways or to cell adhesion molecules like LFA-1 or ICAM-1.
Active ingredient B:
The p38 kinase inhibitors within the scope of the present invention the are compounds chosen from those disclosed in US Patents 6,319,921, 6,358,945, 5,716,972, US 5,686,455, US 5,656,644, US 5,593,992, US 5,593,991, US 5,663,334, US 5,670,527, US 5,559,137, 5,658,903, US 5,739,143, US 5,756,499, US 6,277,989, US 6,340,685, and US 5,716,955; and PCT applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO 95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO 97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO 97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO 98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO 98/24782, WO
98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO 98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO 98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO 99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO 99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO 99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO 99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO 99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO 99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO 00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO 00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO 00/23072, WO
00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO 00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO 00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO 00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO 00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO 01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO 01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO 01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/36403, WO 01/38314, WO 01/47921, WO 01/27089, DE 19842833, and JP 2000 86657 whose disclosures are all incoφorated herein by reference in their entirety. Within the scope of the invention are any of the aforementioned B compounds in combination with component A in a single pharmaceutical composition or adminstered separately.
Of particular interest for the pharmaceutical compositions according to the invention are those p38 inhibitors disclosed in 6,319,921, 6,358,945, US 6,277,989, US 6,340,685, WO 00/12074, WO 00/12497, WO 00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO 00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO
01/38314, WO 01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO 00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO 99/01131, WO 00/43384, WO 00/55152, WO 00/55139 and WO 01/36403.
In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and p38 kinase inhibitor B chosen from the compounds of formula disclosed in WO 00/43384 and corresponding US patent 6,319,921:
wherein
Ar1 is a heterocyclic group selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene; and wherein Aii may be substituted by one or more Rl5R or R3;
Ar2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R2 groups;
L, a linking group, is a
C1-10 saturated or unsaturated branched or unbranched carbon chain; wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C1-4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
is selected from the group consisting of:
a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C1-6 alkyl and C1-6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4- dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetrarnethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of Cue alkyl, C1-6 alkoxy, hydroxy, mono- or di-(Cι- alkyl)amino-C1-3 alkyl, phenylamino-C1-3 alkyl and C1-3 alkoxy-C1-3 alkyl; c) C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl, C1-5 alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)r, phenyl-S(O)t, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
is selected from the group consisting of: (a) C3-10 branched or unbranched alkyl, which may optionally be partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, cyano, C1- alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C1-3)alkylaminocarbonyl; (b) C3-7 cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which may optionally be partially or fully halogenated and which may optionally be substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from O,
S, CHOH, >C=O, >C=S and H; (c) C3-1o branched alkenyl which may optionally be partially or fully halogenated, and which is optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from halogen, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, cyano, C1- alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C1-3)alkylaminocarbonyl; (d) C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three Cι-3 alkyl groups; (e) cyano; and, (f) methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl; R2 is selected from the group consisting of: a Cι-6 branched or unbranched alkyl which may optionally be partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, which may optionally be partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
R3 is selected from the group consisting of: a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl; wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a Cι_ 6 branched or unbranched alkyl, phenyl, naphthyl, heterocycle selected from the group hereinabove described, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl Cι-5 alkyl, naphthyl C1-5 alkyl, halo, hydroxy, cyano, C1-3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-5 alkyl- C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, amino-S(O)2, di-(C1-3)alkylamino-S(O)2, t -C1-5 alkyl, R5 -C1-5 alkoxy, R6- C(O)-C1-5 alkyl and R7 -C1-5 alkyl(R8)N; b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halo, cyano, C1-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, CM alkyl-OC(O),
C1-5 alkyl-C(O)-C1-4 branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R9 -C1-5 alkyl, R10- ..5 alkoxy, Rn-C(O)-C1-5 alkyl, and R12-C1-5 alkyl(R13)N; c) cycloalkyl selected from the group consisting of cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, which the cycloalkyl may optionally be partially or fully halogenated and which may optionally be substituted with one to three C1-3 alkyl groups; d) C5.7 cycloalkenyl, selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group may optionally be substituted with one to three C1-3 alkyl groups; and e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; f) C1-6 branched or unbranched alkyl which may optionally be partially or fully halogenated;
or Rt and R2 taken together may optionally form a fused phenyl or pyridinyl ring,
and wherein each Rs, RB is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl which may optionally be partially or fully halogenated;
each t, R5, Re, R7, R9, R10, Rπ and R12 is independently selected from the group consisting of: morpholine, piperidine, piperazine, imidazole and tetrazole;
m = 0, 1, 2; r = 0, 1, 2; t - 0, 1, 2;
X = O or S and physiologically acceptable acids or salts thereof.
In a preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl.
A more preferred subgeneric aspect of the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein Ar2 is naphthyl.
A yet more preferred subgeneric aspect of the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein: Ai\ is thiophene or pyrazole; Ar2 is 1 -naphthyl;
L is C1-6 saturated or unsaturated branched or unbranched carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C1- branched or unbranched alkyl which may be substituted by one or more halogen atoms; Ri is selected from the group consisting of C1-4alkyl branched or unbranched, cyclopropyl and cyclohexyl which may optionally be partially or fully halogenated and which may optionally be substituted with one to three C1- alkyl groups; R3 is selected from the group consisting of C3-10alkyl branched or unbranched, cyclopropanyl, cyclopentanyl, phenyl, pyridinyl each being optionally substituted as described above and alkoxycarbonylalkyl.
A yet further preferred subgeneric aspect of the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein Ari is pyrazole.
A still yet further preferred subgeneric aspect of previous the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds as immediately discribed above and wherein L is C1-5 saturated carbon chain wherein one or more methylene groups are optionally independently replaced by O,N or S; and wherein said linking group is optionally substituted with 0-2 oxo groups and one or more C branched or unbranched alkyl which may be substituted by one or more halogen atoms.
Particularly preferred embodiments of L are propoxy, ethoxy, methoxy, methyl, propyl, C3-5 acetylene or methylamino each being optionally substituted are described herein.
A more particularly preferred embodiment of L is ethoxy optionally substituted.
The following compounds are representative of the compounds of component B in the compositions according to the invention:
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(2-morpholin-4-yl-ethoxy)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(cis-2,6-dimethylmorpholin-4- yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmorpholin-4- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholin-4- yl)ethoxy)naphthalen-l-yl]-urea; l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2- oχoethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-2- methylethoxy)naphthalen- 1 -yl] -ur ea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl)-l- methylethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-thiomorpholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(l-oxothiomorpholin-4- yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)-3- methylnaphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(2-piρeridin-4-yl-ethoxy)naphthalen-l- yl]-urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-ρyrazol-3-yl]-3-[4-(2-(l-acetylpiperidin-4- yl)ethoxy)naphthalen-l-yl]-urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(2-thiazolidin-3 -yl-ethoxy)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(morpholin-4-yl- carbonyloxo)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(tetrahydropyran-4- yl)ethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-ρyrazol-3-yl]-3-[4-(2-(N-methyl-2- methoxyethylamino)ethoxy)naphthalen- 1 -yl]-urea; l-[5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(2-(l-oxo-tetrahydrothiophen-3- yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-morpholin-4-yl-propyl)naphthalen-l- yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-methyl)naphthalen-l- yl]-urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -thiazolidin-3 -yl-propyl)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydopyran-2-yl- oxy)propyl)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-l-yl]- urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-ρyridin-4-yl-ethenyl)naphthalen-l-yl]- urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)propyn-l- yl)naphthalen- 1 -yl] -urea;
1 -[5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -(tetrahydropyran-2-yl-oxy)prop yn- 1 - yl)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(methoxymethyloxy)propyn-l- yl)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3-methylproρyn-l- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(morpholin-4-yl)-3,3-dimethylpropyn- l-yl)naphthalen-l -yl]-urea; l-[5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(tetrahydropyran-2-yl-oxy)butyn-l- yι)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(3-(furan-2-ylcarbonyloxy)proρyn-l- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piρerdin-l-yl)ρroρyn-l- yl)naphthalen- 1 -yl] -urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -(2-methoxymethylmorpholin-4- yl)propyn- 1 -yl)naρhthalen- 1 -yl] -urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(pyridin-4-yl-methoxy)naphthalen- 1 -yl] - urea;
1 -[5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(2-pyridin-4-yl-ethoxy)naphthalen- 1 -yl] -
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -pyridin-4-yl-propoxy)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol-l-yl-ethoxy)naphthalen-l- yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-benzimidazol-l-yl-ethoxy)naphthalen- l-yl]-urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)- ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-l- yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-carbonylammo)naphthalen- l-yl]-urea; l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(morpholin-4-yl-acetamido)naphthalen-l- yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-3-yl-methylamino)naphthalen-l- yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-3-yl-carbonylamino)naphthalen- l-yl]-urea;
l-[5-iso-Propyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen-l- yl]-urea;
1 - [5 -(Tetrahydropyran-3 -yl)-2-phenyl-2H-pyrazol-3 -yl] -3 -[4-(2-morpholin-4-yl- ethoxy)naphthalen-l-yl]-urea;
l-[5-cyclohexyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-l- yl]-urea;
l-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
1 - [5 -( 1 -methylcycloprop- 1 -yl)-2-phenyl-2H-pyrazol-3 -yl] -3 - [4-(2-morpholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-ethoxycarbonyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-(l-methylcyclohex-l-yl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-l- yl]-urea;
l-[5-tert-butyl-2-benzyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen-l- yl]-urea; l-[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen-l- yl]-urea;
l-[5-tert-butyl-2-(ethoxycarbonylmethyl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(4-methyl-3-(2-ethoxycarbonylvinyl)phenyl)-2H-pyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(4-methyl-3-(moφholin-4-yl)methylphenyl)-2H-ρyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(3-(2-moφholin-4-yl-ethyl)phenyl)-2H-ρyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(3-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4- yl-ethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-(4-(tetrahydropyran-4-ylamino)phenyl)-2H-pyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(4-(3-benzylureido)phenyl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen-l-yl]-urea; 1 - [5 -tert-butyl-2-(2-chloropyridin-5 -yl)-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-ρyridin-4-yl- ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6- dimethylmoφholin-4-yl) ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-moφholin-4-yl- propyn- 1 -yl)naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-dimethylaminomethylmoφholin-4- yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-iso-propyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(thiophen-3-yl)-2H-ρyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-cyclopentyl-2H-ρyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea; l-[5-tert-butyl-2-iso-propyl-2H-pyrazol-3-yl]-3-[4-(tetrahyropyran-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
1 - [5 -tert-butyl-2-cyclopropyl-2H-pyrazol-3 -yl] -3 - [4-( 1 -oxo-tetrahydrothiophen-3 -yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(thiophen-3-yl)-2H-pyrazol-3-yl]-3-[4-(2-ρyridinyl-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-cyclopentyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen-l- yl]-urea;
1 - [5-tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -(pyridin-4-yl)propyn- 1 -yl)naphthalen- l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-methylaminopyridin-4-yl)propyn-l- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(l-oxo-tetrahydothiophen-3- yl)propyn- 1 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(thiazolidin-3-yl)propyn-l- yl)naphthalen- 1 -yl] -urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -(tetiahydropyran-4-yl)propyn- 1 - yι)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl- methoxy)naphthalen- 1 -yl] -urea;
1 -[5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(2-(2-methylaminopyrimidin-4- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-l- yl)ethoxy)naphthalen- 1 -yl] -urea; l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methylaminobenzimidazol-l- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-l- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-[l,8]naphthyridin-4- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-ρyrano[2,3- b]pyridin-5-yl)ethoxy)naphthalen-l-yl]-urea;
1 - [5 -tert-Butyl-2-pyridin-3 -yl-2H-pyrazol-3 -yl] -3 - [4-(2-methylaminopyrimidin-4-yl- methoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-(2-methylρyridin-5-yl) -2H-pyrazol-3-yl]-3-[4-(2-(2- methylaminopyrimidin-4-yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4- methoxybenzimidazol- 1 -yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(4- methylaminobenzimidazol- 1 -yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5- b]ρyridin- 1 -yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-[l,8]naρhthyridin-4- yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H- pyrano[2,3-b]pyridin-5-yl)ethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-cyclopropyl -2H-pyrazol-3-yl]-3-[4-(2-methylaminopyrimidin-4-yl- methoxy)naphthalen- 1 -yl] -urea; l-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(2-methylaminopyrimidin-4- yl)ethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-cyclopropyl-2H-pyrazol-3-yl]-3-[4-(2-(4-methoxybenzimidazol-l- yl)ethoxy)naphthalen- 1 -yl] -urea;
1 - [5 -tert-Butyl-2-cyclopropyl-2H-pyrazol-3 -yl] -3 - [4-(2-(4-methylaminobenzimidazol- 1 - yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-(2-imidazo[4,5-b]pyridin-l- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-methyl-2H-ρyrazol-3-yl]-3-[4-(2-[l,8]naphthyridin-4- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dihydro-2H-pyrano[2,3- b]pyridin-5-yl)ethoxy)naphthalen- 1 -yl]-urea
and their physiologically acceptable acids or salts thereof.
In a particularily preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds:
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen-l- yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(cis-2,6-dimethylmoφholin-4- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6-dimethylmoφholin-4- yl)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(2-(methoxymethyl)moφholin-4- yl)ethoxy)naphthalen-l-yl]-urea; l-[5-tert-Butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4- 2-(moφholin-4-yl)-2- oxoethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-ρyrazol-3-yl]-3-[4- 2-(moφholin-4-yl)-2- methylethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-ρyrazol-3-yl]-3-[4- 2-(moφholin-4-yl)- 1 - methylethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4- 2-thiomoφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4- 2-(l -oxothiomoφholin-4- yl)ethoxy)naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl]-3-[4- 2-moφholin-4-yl-ethoxy)-3 - methylnaphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-< 2-(moφholin-4-yl- carbonyloxo)ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4- 2-(tetrahydropyran-4- yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-ι 2-(l -oxo-tetrahydrothiophen-3 - yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-l 3 -moφholin-4-yl-propyl)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4- moφholin-4-yl-methyl)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethyl)naphthalen-l-yl] urea; l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(moφholin-4-yl)proρyn-l- yl)naphthalen- 1 -yl] -urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 -[4-(3 -(tetrahydropyran-2-yl-oxy)propyn- 1 - yl)naphthalen- 1 -yl] -urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -(tetrahydropyran-2-yl-oxy)butyn- 1 - yl)naphthalen- 1 -yl] -urea;
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(piperdin- 1 -yl)propyn- 1 - yl)naphthalen- 1 -yl] -urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -(2-methoxymethylmoφholin-4- yl)propyn- 1 -yl)naphthalen- 1 -yl] -urea;
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methoxy)naphthalen- 1 -yl]- urea;
l-[5-tert-Butyl-2-ρ-tolyl-2H-ρyrazol-3-yl]-3-[4-(2-pyridin-4-yl-ethoxy)naphthalen-l-yl]- urea;
1 - [5 -tert-Butyl-2-p-tolyl-2H-p yrazol-3 -yl] -3 - [4-(3 -pyridin-4-yl-propoxy)naphthalen- 1 - yl]-urea;
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-imidazol- 1 -yl-ethoxy)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(3,4-dimethoxyphenyl)- ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalen-l- yl]-urea;
l-[5-iso-Propyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen-l- yl]-urea; 1 - [5-cyclohexyl-2-phenyl-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4-yl-ethoxy)naphthalen- 1 - yl]-urea;
l-[5-(2,2,2-trifluoroethyl)-2-phenyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
1 - [5-( 1 -methylcycloprop- 1 -yl)-2-phenyl-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
1 - [5 -( 1 -methylcyclohex- 1 -yl)-2-phenyl-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
1 -[5 -tert-butyl-2-methyl-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4-yl-ethoxy)naphthalen- 1 - yl]-urea;
1 - [5 -tert-butyl-2-(4-chlorophenyl)-2H-pyrazol-3 -yl] -3 -[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-butyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen-l- yl]-urea;
l-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(4-methyl-3-(moφholin-4-yl)methylphenyl)-2H-ρyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(4-methyl-3-dimethylaminomethylphenyl)-2H-pyrazol-3-yl]-3-[4-(2- moφholin-4-yl-ethoxy)naphthalen- 1 -yl]-urea;
1 - [5 -tert-butyl-2-(3 -dimethylaminomethylphenyl)-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4- yl-ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen-l-yl]-urea; l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
1 - [5 -tert-butyl-2-(pyridin-3 -yl)-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl- ethoxy)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(trans-2,6- dimethylmoφholin-4-yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(3-moφholin-4-yl- propyn- 1 -yl)naphthalen- 1 -yl] -urea.
Particularly preferred p38 kinase inhibitors B within the scope of the present invention are the following compounds:
1 -[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen- 1 - yl]-urea;
l-[5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(l-oxothiomoφholin-4- yl)ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-pyridin-4-yl- ethoxy)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-moφholm-4-yl- ethoxy)naphthalen-l-yl]-urea or
1 - [5 -tert-butyl-2-methyl-2H-pyrazol-3 -yl] -3 - [4-(2-moφholin-4-yl-ethoxy)naphthalen- 1 - yl]-urea. In another preferred embodiment the invention relates pharmaceutical combinations comprising compounds A and B, wherein the p38 kinase inhibitor B is selected from the compounds of the formula disclosed in WO 00/55139 and corresponding US patent no. 6,358,945:
wherein:
Ari is selected from the group consisting of: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene;
wherein Art may be substituted by one or more Ri, R or R3;
Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with zero to three R groups;
X is: a) a C5-8 cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 C1- branched or unbranched alkyl, C1-4 alkoxy or C1-4 alkylamino chains; b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy, hydroxy, nitrile, mono- or di-(Cι-3 alkyl)amino, C1-6 alkyl-S(O)m, or halogen;
Y is: a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O) or S and wherein Y is optionally independently substituted with 0-2 oxo groups and one or more C1-4 branched or unbranched alkyl which may be substituted by one or more halogen atoms;
is: a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan, thiophene, pyran, which are optionally substituted with one to three groups consisting of halogen, C1-6 alkyl, Cj-6 alkoxy, hydroxy, mono- or di-(C1-3 alkyl)amino, Cι-6 alkyl-S(O)m , COOH and phenylamino wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C1-6 alkyl and Cι-6 alkoxy; b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4- dioxane, moφholine, thiomoφholine, thiomoφholine sulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone which are optionally substituted with one to three groups consisting of nitrile, C1-6 alkyl, d-6 alkoxy, hydroxy, mono- or di-(Cι. 3 alkyl)amino-C1-3 alkyl, phenylamino-C1-3 alkyl and C1-3 alkoxy-C1- alkyl; c) C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl,
Ci_5 alkoxyalkyl, pyridinyl-C1-3 alkyl, imidazolyl-Cι-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, phenylamino, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
is : a) C3-10 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle selected from the group hereinabove described in this paragraph, and being substituted with 0 to 5 groups selected from the group consisting of halogen,
Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C1_3)alkylaminocarbonyl; b) C3- cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl each being optionally be partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S, CHOH, >CO, >C=S and NH; c) C3-1o branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, Cj-3 alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C1-3)alkylaminocarbonyl; d) a C5- cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups; e) nitrile; or f) C1-6 branched or unbranched alkoxycarbonyl, C1-6 branched or unbranched alkylaminocarbonyl, C1-6 branched or unbranched alkylcarbonylamino-C1-3- alkyl;
is: a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl; R3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl Ci-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, nitrile, C1-3 alkyloxy which may optionally be partially or fully halogenated, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(Ci_ 3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-5 alkyl- C(O)-C1-4 alkyl, amino-Ci-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, amino-S(O)2, di-(C1-3)alkylamino-S(O)2, t -C1-5 alkyl, R5 -C1.5 alkoxy, R<5- C(O)-C1-5 alkyl and R7 -C1.5 alkyl(R8)N, carboxy-mono- or di-(C1-5)-alkyl- amino; b) a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1- 3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-4 alkyl- OC(O), C1-5 alkyl-C(O)-C1-4 branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, R9 -Ci_5 alkyl, R10 -C1-5 alkoxy, Ri i -C(O)-C1-5 alkyl, and R12 -C1-5 alkyl(R13)N; c) cycloalkyl selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups; d) C5-7 cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups; e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl; or f) C1-6 branched or unbranched alkyl optionally partially or fully halogenated;
or Ri and R2 taken together may optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally be partially or fully halogenated;
each Rt, R5, R^, R7, R9, R10, Rπ and R12 is independently selected from the group consisting of moφholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2; W is O or S and pharmaceutically acceptable derivatives thereof.
In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Ari is selected from thiophene and pyrazole;
X is C5-7 cycloalkyl or C5-7cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 CM branched or unbranched alkyl, C1- alkoxy or C1-4 alkylamino; or
X is phenyl, pyridine, tetrahydropyridine, pyrimidine, furan or thiophene each being optionally independently substituted with 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy, hydroxy, nitrile, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl- S(O)m or halogen; Ri is C1-4alkyl branched or unbranched, cyclopropyl or cyclohexyl optionally partially or fully halogenated and optionally substituted with one to three C1- alkyl groups; R3 is C1-4alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl or pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect.
In yet another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: is pyrazole;
X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with an oxo group or 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy or C1-4alkylamino; or X is phenyl, pyridine, furan or thiophene each being optionally independently substituted with 0-3 C1-4 branched or unbranched alkyl, C1-4alkoxy, hydroxy, nitrile, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m or halogen. In yet still another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
Y is -CH2-, -CH2CH2-, -CH2NH-, -CH2CH2NH- or a bond; and Z is phenyl, imidazole, furan, piperazine, tetrahydropyran, moφholine, thiomoφholine, thiomoφholine sulfoxide, piperidine, pyridine, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl and C1-5 alkoxyalkyl, phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m and phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino.
In a further embodiment the invention relates to pharmaceutical combinations comprising
A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring may be substituted by R3;
R3 is C1-4alkyl branched or unbranched, phenyl, pyrimidinyl, pyrazolyl, pyridinyl each being optionally substituted as described hereinabove in the broadest generic aspect, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl optionally substituted as described hereinabove in the broadest generic aspect.
In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein X is pyridinyl.
In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein the pyridinyl is attached to A^ via the 3-pyridinyl position. In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein particular compounds are chosen from:
1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(moφholin-4-yl)phenyl)naphthalen- 1 - yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-ρ-tolyl-2H-ρyrazol-3-yl]-3-[4-(4-(2-(moφholin-4- yl)ethyl)phenyl)naphthalen- 1 -yl]urea;
1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-dimethylaminophenyl)naphthalen- 1 - yfjurea;
1 - [5 -tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -(moφholin-4-yl)phenyl)naphthalen- 1 - yfjurea; l-[5-tert-butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(3-(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-moφholin-4-ylmethyl-pyridin-2- yl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-moφholin-4-ylmethyl-fur-2- yl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-moφholin-4- ylmethyl-pyridin-3 -yl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)naphthalen-l-yl]urea; l-[5-tert-butyl-2-phenyl-2H-ρyrazol-3-yl]-3-[4-(4-piperdin-l-ylmethyl- phenyl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-phenyl-2H-pyrazol-3-yl]-3-[4-(4-(4-methylpiperazin-l- yl)methylphenyl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(3,4-di(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -yl]urea;
1 -[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-ρyridin-4-ylmethyl- pyridin-3 -yl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(l-oxo- thiomoφholin-4-ylmethyl)pyridin-3-yl)naphthalen-l-yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(l-oxo-thiomoφholin-4- ylmethyl)pyridin-3 -yl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-tetrahydropyran-4- ylmethyl -pyridin-3 -yl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(l-oxo- tetrahydrothiophen-3-ylmethyl)pyridin-3-yl)naphthalen-l-yl]urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(imidazol-l- ylmethyl)pyridin-3-yl)naphthalen-l-yl]urea;
l-[2-(3-dimethylaminomethylphenyl)-5-(l-methyl-cyclohexyl)-2H-pyrazol-3-yl]-3-[4-(6- moφholin-4-ylmethyl-pyridin-3-yl)naphthalen-l-yl]urea;
l-[2-(5-(l-methyl-cyclohexyl)-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6- moφholin-4-ylmethyl-pyridin-3 -yl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-moφholin-4-ylmethyl-pyrimidin-5- yl)naphthalen-l-yl]urea; l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-methoxy-5-(2- moφholin-4-yl-ethoxy)phenyl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-moφholin-4-yl- ethoxy)phenyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-nιethyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-3- (dimethylamino)phenyl)naphthalen- 1 -yfjurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-3- (methylsulfonyl)phenyl)naphthalen- 1 -yljurea;
5-tert-butyl-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)naphthalen-l- yl]ureido}thiophene-2-carboxylic acid methyl ester;
5-tert-butyl-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)naphthalen-l- yl]ureido}thiophene-2-carboxylic acid methylamide;
5-tert-butyl-l-methyl-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)naphthalen-l- yl]ureido}-lH-pyrrole-2-carboxylic acid methyl ester;
5-tert-butyl- 1 -methyl-3 - { 3 - [4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)naphthalen- 1 - yl]ureido}-lH-pyrrole-2-carboxylic acid methylamide;
2-acetylamino N-(5-tert-butyl-3- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)naphthalen- 1 -yljureido } thiophen-2-ylmethyl)acetamide;
1 - [5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -moφholin-4-yl-cyclohex- 1 - enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-moφholin-4-yl-cylohept-l- enyl)naphthalen- 1 -yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(2-moφholin-4-yl- ethylamino)cyclohex-l-enyl)naphthalen-l -yljurea; l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-moφholin-4-yl-cyclohept-l- enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(ρyridin-4-yl- methylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(3- (dimethylammoethylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
1 -[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(pyridin-3-yl- methylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(phenyl- methylamino)cyclohex- 1 -enyl)naphthal en- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2- phenylethylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(3-(furan-2-yl- methylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-pyridin-2-yl- ethylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-ylJ-3-[4-(3-(2-piperdin-l-yl- ethylamino)cyclohex- 1 -enyι)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-imidazol-4-yl- ethylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-ylJ-3-[4-(3-(pyridin-2-yl- methylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(3-(2-(4- methoxyphenyl)ethylamino)cyclohex- 1 -enyl)naphthalen- 1 -yljurea; l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-moφholin-4-ylmethyl-3-oxo- cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(4-(l-oxo-tetrahydrothiophen-3- ylmethyl)-3 -oxo-cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(l-oxo-thiomoφholin-4-ylmethyl)-3- oxo-cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(4-methylpiperazin-l-ylmethyl)-3-oxo- cyclohex- 1 -enyl)naphthalen- 1 -yljurea;
1 - [5 -tert-butyl-2-(6-methyl-pyridin-3 -yl)-2H-ρyrazol-3 -ylj -3 - [4- { 6-oxo- 1 -(tetrahydro- pyran-4-ylmethyl)-l,2,3,6-tetrahydro-pyridin-4-yl}naphthalen-l-yl]urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(2-oxo-l-pyridin-4- ylmethyl-piperdin-4-yl)naphthalen- 1 -yljurea;
1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-l -pyridin-4-yl- 1 ,2,3 ,6-tetrahydro- pyridin-4-yl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-oxo-l-pyridin-4-yl- 1 ,2,3 ,6-tetrahydro-pyridin-4-yl)naphthalen- 1 -yljurea;
5-tert-butyl-3- {3-[4-(6-oxo- 1 -ρyridin-4-yl- 1 ,2,3 ,6-tetrahydro-pyridin-4-yl)naphthalen- 1 - ylJureido}thiophene-2-carboxylic acid methyl ester;
5-tert-butyl- 1 -methyl-3- {3-[4-(6-oxo- 1 -pyridin-4-yl- 1 ,2,3,6-tetrahydro-pyridin-4- yl)naphthalen-l-ylJureido}pyrrole-2-carboxylic acid methyl ester;
5-tert-butyl- l-methyl-3- {3-[4-(6-oxo- 1 -pyridin-4-yl- 1 ,2,3,6-tetrahydro-pyridin-4- yl)naphthalen-l-yl]ureido}pyrrole-2-carboxylic acid methyl amide;
5-tert-butyl-3-{3-[4-(3-moφholin-4-yl-cyclohex-l-enyl)naphthalen-l- ylJureido}thiophene-2-carboxylic acid methyl ester; 5-tert-butyl- 1 -methyl-3 - { 3 -[4-(3 -moφholin-4-yl-cyclohex- 1 -enyl)naphthalen- 1 - yl]ureido}pyrrole-2-carboxylic acid methyl ester; and
5 -tert-butyl- 1 -methyl-3 - { 3 - [4-(3 -moφholin-4-yl-cyclohex- 1 -enyl)naphthalen- 1 - yl]ureido}pyrrole-2-carboxylic acid methyl amide and
the pharmaceutically acceptable derivatives thereof.
Preferably the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds:
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(moφholin-4- yl)ethyl)phenyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(3-(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(5-moφholin-4-ylmethyl-ρyridin-2- yl)naphthalen-l-yl]urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-moφholin-4-ylmethyl-fur-2- yl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-moφholin-4- ylmethyl-pyridin-3 -yl)naphthalen- 1 -yljurea;
l-[5-tert-butyl-2-methyl-2H-pyrazol-3-ylJ-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)naphthalen- 1 -yljurea and the pharmaceutically acceptable derivatives thereof.
In another embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds of the formula described in WO 00/55139 and corresponding US patent no. 6,358,945:
wherein:
Ar! is: pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene;
wherein Ari is optionally substituted by one or more R1} R2 or R3;
Ar2 is: phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole each being optionally substituted with zero to three R groups;
X is: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1- alkoxy or Cι-4 alkylamino chains each being branched or unbranched;
phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen; Y is: a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more CM alkyl optionally substituted by one or more halogen atoms;
Z is: aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetiazolyl, furanyl, thienyl and pyranyl, heterocycle selected from piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4- dioxanyl, moφholino, thiomoφholino, thiomoφholino sulfoxidyl, thiomoφholino sulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl, each of the aforementioned Z are optionally substituted with one to three halogen, Cι-6 alkyl, Cι-6 alkoxy, C1-3 alkoxy-Cι-3 alkyl, C1-6 alkoxycarbonyl, aroyl, heteroaroyl, heterocycleC1-3acyl wherein the heteroaryl and heterocycle are as defined hereinabove in this paragraph, C1-3acyl, oxo, hydroxy, pyridinyl-Cι-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, amino-S(O)m, β alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-C1-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by amino -ealkyl, C1-3alkyl, arylC0-3alkyl, C1-5 alkoxyC1-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m- or arylC0-3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)arnino; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy; or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by C1-6alkyl, aminoC1-6alkyl, arylC0-3alkyl, C1-5 alkoxyCι-3 alkyl, C1-5 alkoxy, aroyl, C1-3acyl, Cι_3alkyl-S(O)ra- , arylC0-3alkyl-S(O)m- , nitrileC1-4alkyl or C1-3alkoxyC1-3alkyl, each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkoxyheteroarylCo-3alkyl, heteroarylC0- alkyl or heterocycyleC0-3alkyl wherein the heteroaryl and heterocycle is hereinabove described in this paragraph, or Z is C1-6alkyl branched or unbranched, C1-6alkoxy, C1-3acylamino, nitrileC1- alkyl, Cι-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
is : a) C1-10 branched or unbranched alkyl optionally partially or fully halogenated, and optionally substituted with one to three phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl; each such phenyl, naphthyl or heterocycle, selected from the group hereinabove described, being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, C3-8 cycloalkyl, C5-8 cycloalkenyl, hydroxy, nitrile, C1-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O) and di(C 1 -3)alkylaminocarbonyl ; b) C3- cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S, CHOH,
>CO, >C=S andNH; c) C3.10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1-5 branched or unbranched alkyl, phenyl, naphthyl or heterocyclic groups, with each such heterocyclic group being independently selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each such phenyl, naphthyl or heterocyclic group being substituted with 0 to 5 groups selected from the group consisting of halogen, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, hydroxy, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, NH2C(O) and mono- or di(C1-3)alkylaminocarbonyl; d) a C5- cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups; e) nitrile; or f) C1-6 branched or unbranched alkoxycarbonyl, C1-6 branched or unbranched alkylaminocarbonyl, Cι-6 branched or unbranched alkylcarbonylamino-Cι.3- alkyl;
R2 is: a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile, or R is acetyl, aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl;
R3 is: a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetiahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, wherein such phenyl, naphthyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, naphthyl, heterocycle selected from the group hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl
C1.5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, Cι- alkoxy optionally partially or fully halogenated,
C1.3 alkoxyC1-5alkyl, C1-3thioalkyl, Cj-sthioalkyld-salkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1-5 alkyl-C(O)-C1- alkyl, amino-Q-s alkyl, mono- or di-(C1-3)alkylamino-C1.5 alkyl, amino-S(O)2, di-(C1-3)alkylamino-S(O)2,
R, -Cι.5 alkyl, R5 -C1-5 alkoxy, R6-C(O)-C1-5 alkyl and R7 -C1-5 alkyl(R8)N, carboxy-mono- or di-(C1-5 )-alkyl-amino; a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heterocyclyl selected from the group consisting of cyclopentenopyridine, cyclohexanopyridine, cyclopentanopyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclohexanopyridazine, cyclopentanoquinoline, cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohexanoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene; wherein the fused aryl or fused heterocyclyl ring is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the group hereinabove described, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described, NH2C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C alkyl-OC(O), C1-5 alkyl-C(O)-C branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(Cι-
3)alkylamino-C1-5 alkyl, R -C]-5 alkyl, R10-Cι-5 alkoxy, Rπ -C(O)-C1-5 alkyl and R12 -C1-5 alkyl(R )N; c) cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bi cycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three C1- alkyl groups; d) C5- cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three C1-3 alkyl groups; e) acetyl, aroyl, C1-6alkoxycarbonylCι-6alkyl or phenylsulfonyl; or f) C1-6 branched or unbranched alkyl optionally partially or fully halogenated;
or R\ and R2 taken together optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C branched or unbranched alkyl optionally partially or fully halogenated;
each Rt, R5, Re, R7, R9, Rιθ! Rπ and R12 is independently selected from the group consisting of moφholine, piperidine, piperazine, imidazole and tetrazole;
m is 0, 1 or 2; W is O or S; wherein X is directly attached to one or two -Y-Z, and pharmaceutically acceptable derivatives thereof.
In another embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Ar2 is naphthyl, tetrahydronaphthyl, indanyl or indenyl and W is O.
In another embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: Aii is thiophene or pyrazole each substituted independently by one to three Ri, R2 or
R3;
X is: a C5- cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three CM alkyl, C1-4 alkoxy or CM alkylamino chains each being branched or unbranched;
phenyl, indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl, tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperdinyl, benzimidazole or piperazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitrile, amino, mono- or di-(C1- alkyl)amino, mono- or di-(Cι_3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is: a bond or a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more C atoms are optionally replaced by O or N, and wherein Y is optionally independently substituted with one to two oxo groups, nitrile, phenyl, hydroxy or one or more C alkyl optionally substituted by one or more halogen atoms;
Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl and thienyl, heterocycle selected from piperazinyl, 2-oxa-5-aza-bicyclo[2.2.1Jheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, moφholino, thiomoφholino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-C1-3 alkyl, C1-6 alkoxycarbonyl, aroyl, moφholinocarbonyl, C1- acyl, oxo, hydroxy, pyridinyl-Cι-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, amino-S(O)m, C1-6 alkyl-S(O)m or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-Cι-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylCo-3alkyl, d.5 alkoxyCι-3 alkyl, d-5 alkoxy, aroyl, C1-3acyl, C1-3alkyl-S(O)m- or arylC0-3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group are optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy; or Z is optionally substituted with one to three aryl, heterocycle or heteroaryl as hereinabove described in this paragraph each in turn is optionally substituted by halogen, C1-6 alkyl or C1-6 alkoxy; or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by aroyl, C1-3acyl, C1-6alkyl, C1.5 alkoxyC1-3 alkyl, pyridinylC1-3alkyl, tetiahydrafuranylC1-3alkyl, nitrileC1-4alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, or Z is C1-6alkyl branched or unbranched, C1-6alkoxy or nitrileC1- alkyl;
is:
C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH;
C3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three d-5 branched or unbranched alkyl;
cyclopentenyl and cyclohexenyl optionally substituted with one to three C1-3 alkyl groups;
is: a C1-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl d_5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkoxy optionally be partially or fully halogenated, C1-3 alkoxyC1-5alkyl, C1-3thioalkyl, C1-3thioalkyld. 5alkyl, phenyloxy, naphthyloxy, heteraryloxy wherein the heterocyclic moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH C(O), a mono- or di-(C1-3)alkyl aminocarbonyl, C1.5 alkyl- C(O)-C1-4 alkyl, amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1-5 alkyl, amino-S(O)2, di-(d-3)alkylamino-S(O)2,
P -C1-5 alkyl, R5 -C1-5 alkoxy, R6-C(O)-C1-5 alkyl and R7 -C1-5 alkyl(R8)N, carboxy-mono- or di-(Cι.5 )-alkyl-amino; a fused aryl selected from the group consisting of benzocyclobutanyl, indanyl, indenyl; wherein the fused aryl is substituted with 0 to 3 groups independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, and isothiazolyl, C1-6 branched or unbranched alkyl which is optionally partially or fully halogenated, halogen, nitrile, C1-3 alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyl oxy wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3)alkylamino, phenylamino, naphthylamino, heterocyclylamino wherein the heterocyclyl moiety is selected from the group hereinabove described in this paragraph, NH2C(O), a mono- or di-(Cι-3)alkyl aminocarbonyl, C1-4 alkyl- OC(O), C1-5 alkyl-C(O)-C1-4 branched or unbranched alkyl, an amino-C1-5 alkyl, mono- or di-(C1-3)alkylamino-C1.5 alkyl, R9 -C1-5 alkyl, R10 -d-5 alkoxy, Rπ - C(O)-C1-5 alkyl and R12 -C1-5 alkyl(R13)N;
cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, wherein the cycloalkyl is optionally partially or fully halogenated and optionally substituted with one to three Cι-3 alkyl groups;
C \ -6alkoxycarbonylC \ -6alkyl;
or Rt and R2 taken together optionally form a fused phenyl or pyridinyl ring;
each R8 and R13 is independently selected from the group consisting of: hydrogen and C1-4 branched or unbranched alkyl optionally partially or fully halogenated; and each , R5, R6, R7, R9, R10> Rπ and R12 is independently selected from the group consisting of moφholine, piperidine, piperazine, imidazole and tetrazole;
wherein X is directly attached to one -Y-Z.
In another embodiment the invention relates to pharmaceutical combinations comprising
A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein: An is pyrazole;
X is: cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted with an oxo group or one to three Cι-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
phenyl, furanyl, thienyl, pyridinyl, pyrazinyl piperidinyl or pyrimidinyl each being optionally independently substituted with one to three C1-2 alkyl, C1-2alkoxy, hydroxy or halogen;
is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1Jheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydiOpyranyl, piperazinyl, moφholino, thiomoφholino, thiomoφholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, C1-3 alkoxy-d-3 alkyl, C1-6 alkoxycarbonyl, aroyl, moφholinocarbonyl, Cι-3acyl, oxo, hydroxy, pyridinyl-d-3 alkyl, imidazolyl-d-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkylamino, amino-S(O)m, C1-6 alkyl- S(O)m, or ρhenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino; or Z is optionally substituted with one to three amino, aminocarbonyl or amino-Cι-3 alkyl wherein the N atom is optionally independently mono- or di-substituted by aminoC1-6alkyl, C1-3alkyl, arylC0-3alkyl, Cι-5 alkoxyC1-3 alkyl, d-s alkoxy, aroyl, C1-3acyl, d.3alkyl-S(O)m-, pyridinylC0-3 alkyl, tetrahydrafuranylC0-3 alkyl, or arylCo-3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy; or Z is hydroxy, hydroxyC1-3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by Cι-6alkyl, pyridϊnylCo-3alkyl, tetrahydrafuranylC0.3alkyl, C1-5 alkoxyC1-3 alkyl, C1-3acyl, nitrileC1- alkyl or phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(d.3 alkyl)amino, or Z is Cι-6alkyl branched or unbranched, or nitrileC1-4alkyl;
C1-4 branched or unbranched alkyl optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl optionally partially or fully halogenated and optionally substituted with one to three d-3 alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are replaced by groups independently selected from the group consisting of O, S and NH; C3-10 branched alkenyl optionally partially or fully halogenated and optionally substituted with one to three C1-3 branched or unbranched alkyl;
cyclopentenyl and cyclohexenyl optionally substituted with one to three C1-3 alkyl groups;
R2 is: a Cι-6 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
R3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of a phenyl, heterocycle selected from the group hereinabove described in this paragraph, Cι-6 branched or unbranched alkyl which is optionally partially or fully halogenated, phenyl d.5 alkyl, halogen, hydroxy, oxo, nitrile, d-3 alkoxy optionally partially or fully halogenated, Ci ^thioalkyl, d-sthioalkyld-salkyl, amino, mono- or di-(C1-3)alkylamino, NH2C(O) or a mono- or di-(C1-3)alkyl aminocarbonyl,
d.6alkoxycarbonylC1-6alkyl; or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three d-3 alkyl groups
or R] and R taken together optionally form a fused phenyl or pyridinyl ring.
In another embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
Y is -CH2-, -O-(CH2)o-3-, -CH2CH2-, -CH2NH-, -CH2CH2-NH-, NH-CH2CH2-, -CH2-NH-CH2-, -NH-, -NH-C(O)-, -C(O)-, -CH(OH)-, -CH2(CH2CH3)- or a bond; X is: cyclohexenyl optionally substituted with an oxo group or one to three C1-4 alkyl, CM alkoxy or CM alkylamino chains each being branched or unbranched;
phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with one to three Cι_2 alkyl, C1-2alkoxy, hydroxy or halogen;
Z is: phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2. ljheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, moφholino, thiomoφholino, thiomoφholino sulfoxide and piperidinyl, each of the aforementioned Z are optionally substituted with one to three halogen, d-6 alkyl, C1-6 alkoxy, d-3 alkoxy-d.3 alkyl, C1-6 alkoxycarbonyl, aroyl, moφholinocarbonyl, d^acyl, oxo, hydroxy, pyridinyl-Cι_3 alkyl, imidazolyl-d-3 alkyl, tettahychofuranyl-d-3 alkyl, nitrile-C1-3 alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, amino-S(O)m, C1-6 alkyl- S(O)m, or phenyl-S(O)m wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(d_3 alkyl)amino; or Z is optionally substituted with one to three amino or aminocarbonyl wherein the N atom is optionally independently mono- or di-substituted by aminod-δalkyl, d-
3alkyl, arylC0-3 alkyl, C1-5 alkoxyd-3 alkyl, d-5 alkoxy, aroyl, C^acyl, Ci^alkyl- S(O)m- or arylC0-3alkyl-S(O)m- each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted with one to two halogen, C1-6 alkyl or
C1-6 alkoxy; or Z is hydroxy, hydroxyd.3alkyl, halogen, nitrile, amino wherein the N atom is optionally independently mono- or di-substituted by Cι-3alkyl, pyridinylC1-2alkyl, tetrahydrafuranylC1- alkyl, Cj.3 alkoxyd-3 alkyl, C1-3acyl, nitrileC1- alkyl, phenyl wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, or Z is C1-6alkyl branched or unbranched, C1-6alkoxy or nitrileC1-4alkyl;
Ri is:
CM branched or unbranched alkyl optionally partially or fully halogenated; R2 is: a d-3 branched or unbranched alkyl optionally partially or fully halogenated and optionally substituted with nitrile;
R3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to five groups selected from the group consisting of Cι-3 branched or unbranched alkyl which is optionally partially or fully halogenated, d-3 alkoxy which optionally partially or fully halogenated, d. 3thioalkyl, d-sthioalkyld-salkyl, amino or NH2C(O);
C ^alkoxycarbonyl;
or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three -3 alkyl groups.
In a further embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
Art is 5-tert-butyl-pyrazol-3-yl; wherein the pyrazole ring is substituted independently by one to two R or R3; X is: cyclohexenyl; phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl each being optionally independently substituted with C1- alkoxy or hydroxy;
Z is: phenyl, heteroaryl selected from pyridinyl and furanyl, heterocycle selected from 2-oxa-5-aza-bicyclo[2.2.1Jheptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl, moφholino, thiomoφholino and piperidinyl, each of the aforementioned Z are optionally substituted with one to three d-3 alkyl, C1-3 alkoxy, oxo , hydroxy or NH2C(O)-; or Z is hydroxyC1-3alkyl, amino wherein the N atom is optionally independently mono- or di-substituted by pyridinylmethyl, tetrahydrafuranylmethyl, C1-3 alkoxyd-3 alkyl, C1-3acyl or nitrileC1-4alkyl, or Z is nitrileC1- alkyl;
R3 is: phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, and pyrazolyl, wherein such phenyl or heterocyclic group is optionally substituted with one to two groups selected from the group consisting of C1-2 alkyl which is optionally partially or fully halogenated, C1-2 alkoxy which optionally partially or fully halogenated, C1-2thioalkyl, C1-2thioalkylC1-3alkyl, amino or NH2C(O);
Cι-3alkoxycarbonyl;
or R3 is cyclopropyl or cyclopentyl each optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups.
In a still further embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein X is pyridinyl.
In a yet still further embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein the pyridinyl is attached to A^ via the 3- pyridinyl position.
Preferably the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from:
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-moφholin-4-yl-methylphenyl)- naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[3-(4-moφholin-4-yl-methylρhenyl)- naphthalen- 1 -yl] -urea; l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(5-moφholin-4-yl-methylfuran-2-yl)- naphthalen- 1 -yl]-urea;
L[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(moφholin-4-yl- methyl)cyclohexenyl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(4-moφholin-4-yl)ethylρhenyl)- naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(4-dimethylaminomethylphenyl)- naphthalen- 1 -yl J -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(5-(moφholin-4-yl-methyl)pyridin-2-yl)- naphthalen-l-ylj-urea;
1 - [5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(6-(moφholin-4-yl-methyl)pyridin-3 -yl)- naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-methyl-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl-methyl)pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(moφholin-4- yl)ethylamino)cyclohexenyl)-naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(3,4-(moφholin-4-yl-methyl)phenyl)- naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(4-methylpiperzin-l-yl-methyl)phenyl)- naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(piperdin-l-yl-methyl)phenyl)- naphthalen- 1 -yl] -urea; l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(2-(pyridin-2- yl)ethylamino)cyclohexenyl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(2-(pyridin-4- yl)ethylaminomethyl)phenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-p-tolyl-2H-ρyrazol-3-yl]-3-[4-(4-(ρyridin-3-yl- methylaminomethyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3,4- dimethoxyphenylmethyl)-3 -hydroxyphenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-oxo-l,6-dihydro-pyridin-3- yl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(moφholin-4-yl- methyl)imidazol- 1 -yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(4-(moφholin-4-yl-methyl)imidazol-l- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-ylJ-3-[4-(4-(furan-3-yl-methyl)-3- hydroxyphenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4- hydroxybutylamino)pyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl-methyl)- 3 -hydroxyphenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4- yl-methyl)pyridin-3-yl)naphthalen-l-yl]-urea; l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(imidazol-2-yl- methyl)-3 -hydroxyphenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(4-(3-hydroxymoφholin- 4-yl-methyl)phenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(N-2-methoxyethy-N- methylaminomethyl)ρhenyl)naphthalen- 1 -ylj-urea;
1 - [5 -tert-butyl-2-(6-methyl-pyridin-3 -yl)-2H-pyrazol-3 -yl] -3 - [4-(4-(4-hydroxymoφholin- 4-yl-methyl)phenyl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(3-(moφholin-4-yl- methyl)cyclohexenyl)-naphthalen- 1 -yl] -urea;
1 - [5-tert-butyl-2-(6-methyl-pyridin-3 -yl)-2H-pyrazol-3 -yl] -3 - [4-(4-(tetrahydrofuran-3 -yl- methyl)-3-hydroxyphenyl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2- methoxyethyl)aminomethyl)phenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(3- cyanopropoxy)pyridin-3-yl)naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(4-moφholin-4-yl- methyl-piperdinyl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2- cyanoethyl)aminomethyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(l-moφholin-4-yl-indan-5-yl)- naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3- hydroxyphenyl)naphthalen- 1 -ylj -urea; l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(thiomoφholin-4-yl- methyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(3- carboxamidomoφholin-4-yl-methyl)phenyl)naρhthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo- piperzin- 1 -yl-methyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)ρyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(4- hydroxybutyloxy)pyridin-3-yl)-naphthalen- 1 -ylj-urea;
l-[3-tert-butyl-lΗ-[l,4']bipyrazol-5-yl]-3-[4-(6-(moφholin-4-yl-methyl)ρyridin-3- yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(furan-2-yl-methyl)-3- methoxyphenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(moφholin- 4carbonyl)pyrazin-2-yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran- 4-yl-amino)pyridin-3-yl)-naphthalen- 1 -yl]-urea;
L[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-ylJ-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3-yl)-naphthalen-l -yl]-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2,6- dimethylmoφholin-4-yl-methyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridm-3 -yl)-naphthalen- 1 -ylj -urea; l-[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-oxo-l,6-dihydropyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholm- 4-yl-methyl)pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(moφholin-4-yl-4- carbonyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-oxa-5-aza- bicyclo[2.2.1]heρt-5-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(3-carbamylphenyl)naphthalen-l-ylJ- urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(N-(2-cyanoethyl)-N- (pyridin-3 -yl-methyl)aminomethyl)phenyl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (pyridin-2-yl-methyl)aminomethyl)phenyl)-naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (tetrahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)-4-methoxypyridin-3-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-ylJ-3-[4-(6-(l-moφholin-4-yl- propyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(N-(3- methoxypropyl)amino)pyridin-3-yl)-naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(N-(3- methoxypropyl)-N-methylamino)pyridin-3-yl)-naphthalen-l-yl]-urea; 1 -[3-tert-butyl-l '-methyl- 1Η-[1 ,4']bipyrazol-5-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
1 - [5 -tert-butyl-2-benzyl-2H-pyrazol-3 -yl] -3 - [4-(6-(moφholin-4-yl-methyl)pyridin-3 -yl)- naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-N-di-(2- cyanoethyl)aminomethyl)phenyl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(4-carbamylphenyl)naphthalen-l-yl]- urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(l-oxo- tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(tetrahydropyran-4yl- amino)pyridin-3 -yl)-naphthalen- 1 -ylj -urea;
l-[3-tert-butyl-r-(3-cyanopropyl)-lΗ-[l,4,]bipyrazol-5-ylJ-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3 -yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(3-methanesulfinylphenyl)naphthalen-l- ylj-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(3-methanesulfonylphenyl)naphthalen-l- ylj-urea;
1 - [5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(3 -sulfonamidophenyl)naphthalen- 1 -yl] - urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-(moφholin-4- yl)carbonylphenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(5-(tetrahydrothiopyran- 4yl-amino)pyrazin-2-yl)-naphthalen- 1 -yl] -urea; l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6- (methylcarbonylamino)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl-4-carbonyl)phenyl)- naphthalen- 1 -yl] -urea;
1 -[3-tert-butyl-r-(3-methylsulfanylpropyl)-lΗ-[l ,4']bipyrazol-5-yl]-3-[4-(6-(moφholin- 4-yl-methyl)pyridin-3-yl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(5-(moφholin-4-yl-carbonyl)pyridin-3- yl)-naphthalen- 1 -ylj -urea;
1 - [5 -tert-butyl-2-(6-methyl -pyridin-3 -yl)-2H-pyrazol-3 -yl] -3 -[4-(5 -(moφholin-4-yl- methyl)pyrazin-2-yl)-naphthalen- 1 -yl] -urea;
1 - [5-tert-butyl-2-(6-methyl-pyridin-3 -yl)-2H-pyrazol-3 -yl] -3 - [4-(6-aminopyridin-3 - yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(l-methylpiρerdin-4- yl-amino)pyridin-3-yl)naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo- piperzin- 1 -yl-methyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- carbonyl)pyridin-3-yl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4 6-(N,N-di-(2- methoxyethyl)aminomethyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylρyrimidin-5-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(l-oxo- thiomoφholin-4-yl-methyl)pyridin-3 -yl)naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydropyran-4- yl-amino)pyridin-3-yl)naphthalen-l-yl]-urea; l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(5-(moφholin-4-yl- methyl)pyrazin-2-yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4- yl-methyl)pyridin-3 -yl)naphthalen- 1 -ylj -urea;
1 -[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(2-methyl-3-oxo-piperzin- 1 -yl- methyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
1 - [5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(6-(pyridin-3 -yl-oxy)pyridm-3 - yl)naphthalen- 1 -yl] -urea
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-amino)pyridin-3- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methoxypyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3-yl)naphthalen-l-ylJ-urea;
1 - [5 -tert-butyl-2-p-tolyl-2H-pyrazol-3 -ylj -3 - [4-(5 -carbamylpyridin-3 -yl)naphthalen- 1 - yl]-urea;
l-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(4-(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -yl] -urea;
1 -[3-tert-butyl- 1 '-methyl- 1 Η-[ 1 ,4']bipyrazol-5-ylJ-3-[4-(6-(moφholin-4-yl- methyl)phenyl)naρhthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-(2-cyclopropylpyrimidin-5-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(moφholin-4- yl-methyl)pyridin-3 -yl)naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(pyridin-3-yl-amino)pyrimidin-5- yl)naphthalen- 1 -yl]-urea; l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(l-oxo-tetrahydrothiopyran-4-yl- amino)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomoφholin-4-yl-methyl)pyridin-3- yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(ρyridin-3-yl- methyl)pyridin-3 -yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(2-(moφholin-4-yl-carbonyl)pyrimidin-5- yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(2-(moφholin-4-yl-methyl)pyrimidin-5- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(3-amino-4-carbamylphenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(l-oxo-thiomoφholin-4-yl- methyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(pyridin-3-yl-methyl)pyridin-3- yl)naphthalen- 1 -yl]-urea;
1 - [5-tert-butyl-2-p-tolyl-2H-pyrazol-3 -yl] -3 - [4-(6-(hydroxy-pyridin-3 -yl-methyl)pyridin- 3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(2-(moφholin-4-yl- methyl)pyrimidin-5-yl)naphthalen-l-ylJ-urea; and the pharmaceutically acceptable derivatives thereof. In another embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(5-(moφholin-4-yl-methyl)pyridin-2-yl)- naphthalen-1 -ylj-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl-methyl)pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(3-(2-(pyridin-2- yl)ethylamino)cyclohexenyl)-naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(4-(pyridin-3-yl- methylaminomethyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(moφholin-4-yl- methyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(6-(4- hydroxybutylamino)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(4-methyl-3-carbamylphenyl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4- yl-methyl)pyridin-3-yl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(3-hydroxypiperidin- 1 -yl-methyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(4-hydroxymoφholin- 4-yl-methyl)phenyl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-ρyrazol-3-ylJ-3-[4-(3-(moφholin-4-yl- methyl)cyclohexenyl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(4-(tetiahydrofuran-3-yl- rnethyl)-3-hydroxyphenyl)naphthalen-l-yl]-urea; l-[5-tert-butyI-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(N,N-di-(2- methoxyethyl)aminomethyl)phenyl)naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(3- cyanopropoxy)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-moφholin-4-yl- methyl-piperdinyl)naphthalen- 1 -yl] -urea;
1 -[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N,N-di-(2- cyanoethyl)aminomethyl)phenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(furan-2-yl-methyl)-3- hydroxyphenyl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(thiomoφholin-4-yl- methyl)phenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(3- carboxamidopiperidin- 1 -yl-methyl)phenyl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-ρyrazol-3-yl]-3-[4-(4-(2-methyl-3-oxo- piperzin- 1 -yl-methyl)phenyl)naphthalen- 1 -ylj-urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3-yl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(4- hydroxybutyloxy)pyridin-3-yl)-naphthalen- 1 -ylj-urea;
1 -[3-tert-butyl- 1 'H-[ 1 ,4'Jbipyrazol-5-yl]-3-[4-(6-(moφholin-4-yl-methyl)pyridin-3- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(tetrahydrothiopyran- 4-yl-amino)pyridin-3-yl)-naphthalen-l -ylj-urea; l-[5-tert-butyl-2-(2-cyanoethyl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(2,6- dimethylmoφholin-4-yl-methyl)pyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
1 -[5-tert-butyl-2-(2-aminoypyridin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl-4- carbonyl)pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl-methyl)pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(4-(N-(2-cyanoethyl)-N- (pyridin-3-yl-methyl)aminomethyl)phenyl)-naphthalen-l-ylJ-urea;
l-[5-tert-butyl-2-(6-methyl-pyridm-3-yl)-2H-pyrazol-3-yl]-3-[4-(4-(N-(2-cyanoethyl)-N- (tetiahydrofuran-2-yl-methyl)aminomethyl)phenyl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-ρyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)-4-methoxypyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-yl]-3-[4-(6-(l-moφholin-4-yl- propyl)pyridin-3 -yl)-naphthalen- 1 -ylj -urea;
l-[3-tert-butyl- 1 '-methyl- 1 Η-[ 1 ,4'Jbipyrazol-5-ylJ-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3-yl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(l-oxo- tetrahydrothiopyran-4yl-amino)pyridin-3-yl)-naphthalen- 1 -ylj-urea; l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(tetrahydropyran-4yl- amino)pyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridm-3-yl)-2H-pyrazol-3-ylJ-3-[4-(5-(tetrahydrothiopyran- 4yl-amino)pyrazin-2-yl)-naphthalen- 1 -yl]-urea;
l-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazol-3-ylJ-3-[4-(6- (methylcarbonylamino)pyridin-3-yl)-naphthalen- 1 -yl] -urea;
1 -[3-tert-butyl- 1 '-(3-methylsulfanylpropyl)-lΗ-[ 1 ,4'Jbipyrazol-5-yl]-3-[4-(6-(moφholin- 4-yl-methyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(l-oxo- thiomoφholin-4-yl-methyl)pyridin-3 -yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-(2-methylpyrimidin-5-yl)-2H-pyrazol-3-ylJ-3-[4-(6-(tetrahydropyran-4- yl-amino)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-(2-methylthiopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4- yl-methyl)pyridin-3-yl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-(2-aminopyrimidin-5-yl)-2H-pyrazol-3-yl]-3-[4-(6-(moφholin-4-yl- methyl)pyridin-3-yl)naphthalen- 1 -ylj-urea;
l-[3-tert-butyl-l'-methyl-lΗ-[l,4'Jbipyrazol-5-yl]-3-[4-(6-(moφholin-4-yl- methyl)phenyl)naphthalen-l-ylj-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylJ-3-[4-(6-(l-oxo-tetrahydrothiopyran-4-yl- amino)pyridin-3 -yl)naphthalen- 1 -ylj -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(thiomoφholin-4-yl-methyl)pyridin-3- yl)naphthalen-l-yl]-urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(moφholin-4-yl-carbonyl)pyrimidin-5- yl)naphthalen-l-yl]-urea; l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(2-(moφholin-4-yl-methyl)pyrimidin-5- yl)naphthalen- 1 -yl] -urea;
l-[5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl]-3-[4-(6-(l-oxo-thiomoφholin-4-yl- methyl)pyridin-3 -yl)naphthalen- 1 -yl] -urea;
1 - [5 -tert-butyl-2-(2-methylpyrimidin-5 -yl)-2H-pyrazol-3 -yl] -3 - [4-(2-(moφhoιin-4-yl- methyl)pyrimidin-5-yl)naphthalen-l -yl]-urea and
the pharmaceutically acceptable derivatives thereof.
In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds of formula as disclosed in WO 00/55139 and corresponding US patent no. 6,358,945:
wherein:
G is : an aromatic C6-10 carbocycle or a nonaromatic C .10 carbocycle saturated or unsaturated; a 6-10 membered heteroaryl containing 1 or more heteroatoms chosen from O, N and S; a 5-8 membered monocyclic heterocycle containing one or more heteroatoms chosen from O, N and S; or an 8-11 membered bicyclic heterocycle, containing one or more heteroatoms chosen from O, N and S; wherein G is substituted by one or more Rls R2 or R3;
Ar is: phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl each being optionally substituted by one or more f or R5;
X is: a C5-8 cycloalkyl or cycloalkenyl optionally substituted with one to two oxo groups or one to three CM alkyl, CM alkoxy or C1-4 alkylamino chains;
phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl or pyrazinyl;
Y is: a bond or a CM saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetiazolyl, furanyl, thienyl, pyranyl each being optionally substituted with one to three halogen, Cj-6 alkyl, C1-6 alkoxy, hydroxy, amino, mono- or di- (d.3 alkyl)amino, C1-6 alkyl-S(O)m, CN, CONH2, COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, Cι-6 alkyl or C1-6 alkoxy; tetrahydropyranyl, tetiahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4- dioxanyl, moφholinyl, thiomoφholinyl, thiomoφholino sulfoxidyl, thiomoφholino sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetiahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino-C1-3 alkyl, CONH2, phenylamino-C1-3 alkyl or C1-3 alkoxy-d.3 alkyl; halogen, CM alkyl, nitrile, amino, hydroxy, d-β alkoxy, NH2C(O), mono- or di(C1-3alkyl) aminocarbonyl, mono- or di(C1-6alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to d.3 alkyl or d.5 alkoxyalkyl, pyridinyl-d.3 alkyl, imidazolyl-d-3 alkyl, tetrahydrofuranyl-Cι-3 alkyl, nitrile-Cι_3 alkyl, carboxamide-C1-3 alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
each Rt is independently:
C1-10 alkyl optionally be partially or fully halogenated, and optionally substituted with one to three C3.10 cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to five groups selected from halogen, C1-6 alkyl which is optionally partially or fully halogenated, d-s cycloalkanyl, C5.8 cycloalkenyl, hydroxy, nitrile, d-3 alkoxy which is optionally partially or fully halogenated or NH C(O), mono- or di(Cι-3alkyl)amino, and mono- or di(Cι-3alkyl)aminocarbonyl;
cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, or cycloheptyloxy each being optionally partially or fully halogenated and optionally substituted with one to three -3 alkyl groups optionally partially or fully halogenated, CN, hydroxyCι-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH;
phenyloxy or benzyloxy each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3 alkyl or aryl; or an analog of such cycloaryl group wherein one to two ring methyne groups are independently replaced by N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three C1-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3alkyl or aryl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S(O)m, CHOH, >C=O, >C=S or NH;
C3-10 branched or unbranced alkenyl each being optionally partially or fully halogenated, and optionally be substituted with one to three d-5 branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of the aforementioned being substituted with zero to five halogen, C1-6 alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy, nitrile, d-3 alkyloxy which is optionally partially or fully halogenated, NH2C(O), mono- or di(C1-3alkyl)aminocarbonyl; the C3-10 branched or unbranced alkenyl being optionally interrupted by one or more heteroatoms chosen from O, N and S(O)m;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such cycloalkenyl group is optionally substituted with one to three d-3 alkyl groups;
nitrile, halogen;
methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl;
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated;
C3-6 alkynyl branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrrolidinyl, pyrrolyl, one or more C1-4 alkyl optionally substituted by one or more halogen atoms, nitrile, moφholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetiazolyl, or mono- or di(C1-3alkyl)amino optionally substituted by one or more halogen atoms;
each R2, Rt, and R5 is a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, nitrile, methoxycarbonyl, C1-3 alkyl-S(O)m optionally partially or fully halogenated, or phenylsulfonyl;
Cι-6 alkoxy, hydroxy, amino, or mono- or di-(Cι-4 alkyl)amino, nitrile, halogen;
OR6;
nitro; or
mono- or di-(C1- alkyl)amino-S(O) optionally partially or fully halogenated, or H2NSO2;
each R3 is independently: phenyl, naphthyl, moφholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazoyl, triazolyl, tetiazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthypyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, each of the aforementioned is optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, d. 6 branched or unbranched alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl d-5 alkyl, naphthyl C1-5 alkyl, halogen, hydroxy, oxo, nitrile, C1-3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heterocyclic or heteroaryl moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1-3alkyl) aminocarbonyl, C1-5 alkyl-C(O)-C1- alkyl, amino-C1-5 alkyl, mono- or di-(d-3alkyl)amino-C1-5 alkyl, amino-S(O)2, di-(C1-3alkyl)amino- S(O)2, R7-C1-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-C1-5 alkyl, Rι0-C1-5 alkyl^ N, carboxy-mono- or di-(Cι-5alkyl)-amino; a fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or a fused heteroaryl selected from cyclopentenopyridiiiyl, cyclohexanopyridinyl, cyclopentanopyrimidinyl, cyclohexanopyrimidinyl, cyclopentanopyrazinyl, cyclohexanopyrazinyl, cyclopentanopyridazinyl, cyclohexanopyridazinyl, cyclopentanoquinolinyl, cyclohexanoquinolinyl, cyclopentanoisoquinolinyl, cyclohexanoisoquinolinyl, cyclopentanoindolyl, cyclohexanoindolyl, cyclopentanobenzimidazolyl, cyclohexanobenzimidazolyl, cyclopentanobenzoxazolyl, cyclohexanobenzoxazolyl, cyclopentanoimidazolyl, cyclohexanoimidazolyl, cyclopentanothienyl and cyclohexanothienyl; wherein the fused aryl or fused heteroaryl ring is independently substituted with zero to three phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C1-6 alkyl which is optionally partially or fully halogenated, halogen, nitrile, d-3 alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1- 3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), mono- or di-(C1-3alkyl)aminocarbonyl, CM alkyl-OC(O), d-5 alkyl-C(O)-C1- alkyl, amino-d.5 alkyl, mono- or di-(C1-3)alkylamino-Cι-5 alkyl, R12-C1-5 alkyl, RB-C1-5 alkoxy, R14-C(O)-C1-5 alkyl or R15-C1-5 alkyl(R16)N;
cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each being optionally partially or fully halogenated and optionally substituted with one to three CM alkyl groups, or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH;
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each optionally substituted with one to three CM alkyl groups; C alkyl-phenyl-C(O)-C1-4 alkyl-, C1-4 alkyl-C(O)-C1-4 alkyl- or C1-4 alkyl- phenyl-S(O)m-C1-4 alkyl-;
C1-6 alkyl or C1-6 branched or unbranched alkoxy each of which is optionally partially or fully halogenated or optionally substituted with R1 ;
OR18 or C1-6 alkyl optionally substituted with OR18;
amino or mono- or di-(d.5alkyl)amino optionally substituted with R19;
R20C(O)N(R21>, R22O- or R23R24NC(O)-; R26(CH2)mC(O)N(R21)- or R26C(O)(CH2)mN(R21)-;
C2-6alkenyl substituted by R23R24NC(O)-;
C2-6 alkynyl branched or unbranched carbon chain, optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S(O)m and wherein said alkynyl group is optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, moφholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetiazolyl one or more Cι-4 alkyl optionally substituted by one or more halogen atoms, nitrile, moφholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetiazolyl, or mono- or di(C1-4 alkyl)amino optionally substituted by one or more halogen atoms; or
aroyl;
R6 is a:
C1- alkyl optionally partially or fully halogenated and optionally substituted with R26;
each R7, R8, R9, R10, R12, R13, R14, R15, Rπ, R19, R25 and R26 is independently: nitrile, phenyl, moφholino, piperidinyl, piperazinyl, imidazolyl, pyridinyl, tetiazolyl, amino or mono- or di-(C1- alkyl)amino optionally partially or fully halogenated;
each Rπ andR16 is independently: hydrogen or C1- alkyl optionally partially or fully halogenated;
R18 is independently: hydrogen or a CM alkyl optionally independently substituted with oxo or R25;
R20 is independently:
Ci-io alkyl optionally partially or fully halogenated, phenyl, or pyridinyl;
R21 is independently: hydrogen or C 1.3 alkyl optionally partially or fully halogenated;
each R22, R23 and R is independently: hydrogen, C1-6 alkyl optionally partially or fully halogenated, said C1-6 alkyl is optionally interrupted by one or more O, N or S, said C1- alkyl also being independently optionally substituted by mono- or phenyl, pyridinyl, amino or mono- or di-(C1-4alkyl)amino each of which is optionally partially or fully halogenated and optionally substituted with mono- or di-(C1-3alkyl)amino; or R23 and R 4 taken together optionally form a heterocyclic or heteroaryl ring;
m = 0, 1 or 2;
W is O or S and pharmaceutically acceptable derivatives thereof.
h another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein
G is: phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl;
pyridinyl, pyridonyl, quinoiinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[l,4Joxazin-3-onyl, benzodioxolyl, benzo[l,3]dioxol-2-onyl, benzofuran-3- onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl; oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, moφholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomoφholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or dithianyl; wherein G is substituted by one or more Rj, R or R3;
In a further preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the ρ38 kinase inhibitor B is selected from the compounds immediately described above and wherein
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indenyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more Rl5 R2 or R3;
Ar is: naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl each being optionally substituted by one or more t or R5 groups;
X is: phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl
Y is: a bond or a C saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more CM alkyl optionally substituted by one or more halogen atoms;
Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, amino, mono- or di-(C1- alkyl)amino, CONH2 or OH;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4- dioxanyl, moφholinyl, thiomoφholinyl, thiomoφholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetiahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, CM alkyl, CM alkoxy, amino, mono- or di-
(C1-3 alkyl)amino, CONH2, or OH; nitrile, C1-6 alkyl-S(O)m, halogen, hydroxy, C1-4 alkoxy, amino, mono- or di-(C1-6 alkyl)amino, mono- or di-(d-3 alkyl)aminocarbonyl or NH2C(O);
each Rt is independently:
C3-6 alkyl optionally partially or fully halogenated, and optionally substituted with one to three C3-6cycloalkyl, phenyl, thienyl, furyl, isoxazolyl or isothiazolyl; each of the aforementioned being optionally substituted with one to three groups selected from halogen, C1-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or d^alkoxy which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three d-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyd-3alkyl or phenyl; or an analog of such cycloalkyl group wherein one to three ring methylene groups are independently replaced by O, S, CHOH, >C=O, >C=S or NH; or
silyl containing three C1-4 alkyl groups optionally partially or fully halogenated; R2 is independently: halogen, C1-3 alkoxy, C1-3 alkyl-S(O)m optionally partially or fully halogenated, phenylsulfonyl or nitrile;
R3 is independently: phenyl, moφholino, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolylidinyl, imidazolyl, pyrazolyl, each being optionally substituted with one to three phenyl, naphthyl, heterocycle or heteroaryl as hereinabove described in this paragraph, d. β alkyl which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl C1-5 alkyl, naphthyl C1-5 alkyl, halogen, oxo, hydroxy, nitrile, d-3 alkyloxy optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or heterocyclicoxy wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, nitro, amino, mono- or di-(C1-3alkyl)amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino wherein the heteroaryl or heterocyclic moiety is as hereinabove described in this paragraph, NH2C(O), a mono- or di-(C1- alkyl)aminocarbonyl, C1-5 alkyl-C(O)-C1-4 alkyl, mono- or di-(C1-3alkyl)amino, mono- or di-(C1-3)alkylamino-C1-5 alkyl, mono- or di-(C1- alkyl)amino-S(O)2, R - d-5 alkyl, R8-C1-5 alkoxy, R9-C(O)-C]-5 alkyl, R10-Cι-5 alkyl(Ri ι)N, carboxy- mono- or di-(C1-5)-alkyl-amino;
C1-3 alkyl or C1-4 alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or d.6 alkyl optionally substituted with OR18;
amino or mono- or di- (d-5 alkyl) amino optionally substituted with R1 ;
R20C(O)N(R21)-, R22O- ; R23R2 NC(O)-; R26CH2C(O)N(R21)- or
R26C(O)CH2N(R21)-; C2- alkenyl substituted by R23R 4NC(O)-; or
C2- alkynyl branched or unbranched carbon chain optionally partially or fully halogenated and optionally independently substituted with one to two oxo groups, pyrroldinyl, pyrrolyl, moφholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetiazolyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms; and
R23 and R24 taken together optionally form imidazolyl, piperidinyl, moφholinyl, piperazinyl or a pyridinyl ring.
In yet another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein:
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indanyl, indolyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted by one or more Ri, R2 or R3;
Ar is naphthyl;
X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl each being optionally independently substituted with one to three C1-4 alkyl, C1- alkoxy, hydroxy, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(d-3 alkylamino)carbonyl, NH2C(O), Cj-6 alkyl-S(O)m or halogen;
Y is: a bond or a C1- saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group;
Z is: phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy; tetrahydropyranyl, moφholinyl, thiomoφholinyl, thiomoφholino sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetiahydropyrimidonyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy; or
d-3 alkoxy;
each R1 is independently: d-5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl substituted with zero to three halogen, d-3 alkyl which is optionally partially or fully halogenated, hydroxy, nitrile or which is optionally partially or fully halogenated;
cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each being optionally partially or fully halogenated and optionally substituted with one to three d-3 alkyl groups optionally partially or fully halogenated, CN, hydroxyC1-3alkyl or phenyl; and an analog of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl wherein one ring methylene group is replaced by O; and
silyl containing three C1-2 independently alkyl groups optionally partially or fully halogenated;
each R2 is independently: bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile;
each R3 is independently: phenyl, moφholino, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl, pyrazolyl, each of the aforementioned is optionally substituted with one to three d-3 alkyl which is optionally partially or fully halogenated, halogen, oxo, hydroxy, nitrile and C alkyloxy optionally partially or fully halogenated;
Ci_3 alkyl or d-3 alkoxy each being optionally partially or fully halogenated or optionally substituted with R17;
OR18 or C1-3 alkyl optionally substituted with OR18; amino or mono- or di-(d-3 alkyl)amino optionally substituted with R1 ; R20C(O)N(R21)-, R22O- ; R23R2 NC(O)-; R26CH2C(O)N(R21)- or R26C(O)CH2N(R21)-;
C2- alkenyl substituted by R23R24NC(O)-; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl; and R23 and R 4 taken together optionally form moφholino.
In yet another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein
G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl, or indolinonyl, wherein G is substituted by one or more Rls R2 or R3;
Ar is 1 -naphthyl; X is: phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperdinyl, piperazinyl, pyridazinyl or pyrazinyl;
Y is: a bond or
-CH2-, -CH2CH2-, -C(O)-, -O-, -S-, -NH-CH2CH2CH2-, -N(CH3)-, or -NH-;
each Rϋ is independently:
C3-5 alkyl optionally partially or fully halogenated, and optionally substituted with phenyl;
cyclopropyl, cyclopentanyl, cyclohexanyl and bicyclopentanyl optionally substituted with one to three methyl groups optionally partially or fully halogenated, CN, hydroxymethyl or phenyl; or 2-tetiahydrofuranyl substituted by methyl; or trimethyl silyl;
each R3 is independently: phenyl, moφholinyl, pyridinyl, pyrimidinyl, pyrrolylidinyl, 2,5-pyrrolidin-dionyl, imidazolyl or pyrazolyl, wherein any of the aforementioned is optionally substituted with C1-2 alkyl which is optionally partially or fully halogenated;
CM alkyl or C alkoxy each being optionally partially or fully halogenated or optionally substituted with diethylamino;
OR18 or CM alkyl optionally substituted with OR18;
amino or mono- or di-(d.3 alkyl)amino optionally substituted with R19;
CH3C(O)NH-, R22O- ; R23R24NC(O)-; R26CH2C(O)N(R21)- or R26C(O)CH2N(R21)-;
C2-4alkenyl substituted by R23R24NC(O)-; or
C2-4 alkynyl substituted with pyrroldinyl or pyrrolyl;
R23 and R2 are H or R23 and R24 taken together optionally form moφholino; and R26 is moφholino.
h a further preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein G is phenyl, pyridinyl or naphthyl wherein G is substituted by one or more Ri, R2 or R3;
X is: imidazolyl or pyridinyl; Y is:
-CH2-, -NH-CH2CH2CH2- or -NH-;
Z is moφholino;
each Ri is independently: tert-butyl, sec-butyl, tert-amyl or phenyl;
R2 is chloro;
R3 is independently: methyl, methoxy, methoxymethyl, hydroxypropyl, acetamide, moφholino or moφholinocarbonyl.
In yet a further preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein X is pyridinyl.
In yet a still further preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the compounds immediately described above and wherein the pyridinyl is attached to Ar via the 3 -pyridinyl position.
Preferably the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
l-(3-Cyano-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
l-(3-Fluoro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
l-(4-Chloro-2-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-(2-Chloro-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen-l-yl]-urea , l-(3,4-Dimethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ- urea
l-(3-Iodo-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
1 - [4-(6-Moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -ylj -3 -m-tolyl-urea
l-(4-Methylsulfanyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea
l-(3-Chloro-4-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea
l-(4-Chloro-3-nitio-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea
l-(2,5-Dichloro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea
l-[4-(6-Mθφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-naphthalen-2-yl-urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-phenyl-urea
1 -(3 -Chloro-phenyl)-3 - [4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -urea
l-(4-Chloro-3-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(2,4,6-trichloro-phenyl)- urea
l-(2-Methyl-3-nitro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea
1 -(4-Methyl-2-nitro-phenyl)-3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - ylj-urea l-(2,3-Dichloro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ- urea
l-(2-Methoxy-5-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea
1 -(2-Chloro-6-methyl-phenyl)-3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - ylj-urea
l-(2,4-Dichloro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea
1 -(4-Methyl-3 -nitio-phenyl)-3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - yl]-urea
1 -(2,4-Dimethyl-phenyl)-3 - [4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] - urea
l-(2,3-Dimethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea
1 -(4-Cyano-phenyl)-3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -ylj-urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-3-(3,4,5-trimethoxy- phenyl)-urea
l-Biphenyl-4-yl-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
l-(2,5-Difluoro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea
l-(3-Chloro-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- l-yl]-urea l-(2-Fluoro-3-tiifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea
l-(4-Benzyloxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea
l-(2-Methylsulfanyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea
1 -(2-Fluoro-6-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
1 -(4-Fluoro-3 -trifluoromethyl-phenyl)-3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)- naphthalen-1 -ylj-urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(2,4,5-trimethyl-phenyl)- urea
1 - [4-(6-Moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -3 -(4-trifluoromethyl- phenyl)-urea
l-(3-Methylsulfanyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-ρyridin-3-yl)-naphthalen-l- ylj-urea
1 -(2-Methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea
l-(2-Fluoro-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea
l-(4-Methoxy-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- l-yl]-urea
l-(2-Fluoro-5-nitro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea
1 -(4-Ethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -urea l-(2,5-Dimethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea
l-(4,5-Dimethyl-2-nitro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea
l-(5-Chloro-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea
l-(2-Isopropyl-6-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-(2-Difluoromethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naρhthalen- l-yl]-urea
l-(4-Isopropyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ- urea
l-(4-Methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
l-(3-Ethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
l-(2-Ethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea
l-(4-Butoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
4-{3-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-ureido}-benzoic acid ethyl ester
l-(4-Butyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea
l-(2,6-Dibromo-4-isopropyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -ylj -urea 1 -(3-Methoxy-phenyl)-3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl]-urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(4- trifluoromethylsulfanyl-phenyl)-urea
5- { 3 - [4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj -ureido } -isophthalic acid dimethyl ester
l-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen-1 -ylj-urea
3-{3-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-ureido}-benzoic acid ethyl ester
1 -(5-tert-Butyl-2-hydroxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea
l-(2-Hydroxymethyl-4-phenyl-cyclohexyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-(2-Methylsulfanyl-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen-l -ylj-urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(4-pentyloxy-biphenyl-3- yl)-urea
4-Methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-ureido}- benzoic acid methyl ester
l-(2,5-Diethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ- urea
l-Benzothiazol-6-yl-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea
N-(2,5-Diethoxy-4-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- ureido} -phenyl)-benzamide 1 -[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylJ-3-(3-phenoxy-phenyl)-urea
l-(5-Ethanesulfonyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea
4-Methoxy-3 - { 3 -[4-(6-moφholin-4-ylmethyl-pyridm-3 -yl)-naphthalen- 1 -yl] -ureido } -N- phenyl-benzamide
l-(2-Methyl-l,3-dioxo-2,3-dihydro-lH-isoindol-5-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -yl] -urea
l-(2,3-Dimethyl-lH-indol-5-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea
N-Butyl-4-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ- ureido } -benzenesulfonamide
l-[3-(2-Methyl-[l,3]dioxolan-2-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea
l-(3-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-(2,4-Dimethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ- urea
l-(2-Methyl-4-nitio-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea
l-(2-Methoxy-4-nitro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea
1 -(4-Chloro-2-nitio-phenyl)-3 - [4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - yl]-urea l-(5-Chloro-2-methoxy-ρhenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea
l-(3,5-Dimethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ- urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(4-trifluoromethoxy- phenyl)-urea
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-3-(3- trifluoromethylsulfanyl-phenyl)-urea
1 -[4-(6-Moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -3 -(2-phenoxy-phenyl)-urea
1 -(2-Methoxy-5 -nitro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - yl]-urea
l-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
1 -(3 , 5-Bis-trifluoromethyl-phenyl)-3 - [4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)- naphthalen- 1 -ylj -urea
l-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea
l-(3-Methyl-naphthalen-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea
1 -(3 -tert-Butyl-phenyl)-3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -ylj - urea
l-(4-Methyl-biphenyl-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea 1 -(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - ylj-urea
l-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea
l-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea
l-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-ρyridin-3-yl)- naphthalen- 1-yl] -urea
l-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-aminoJ-pyridin-3- yl}-naphthalen-l-yl)-urea
l-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-moφholin-4-ylmethyl-imidazol-l-yl)- naphthalen- 1 -ylj -urea
l-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea
l-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]- naphthalen- 1 -yl} -urea
l-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea l-(5-tert-Butyl-2-moφholin-4-yl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea
l-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen-l -ylj -urea
l-t4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(3-trifluoromethyl- phenyl)-urea
1 -[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylJ-3-(4-trifluoromethoxy- phenyl)-urea
l-[5-(l,l-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen-l -ylj-urea
l-[5-tert-Butyl-2-(lH-pyrazol-4-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea
l-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-yl]-urea
l-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1 -yl]-urea
l-[5-tert-Butyl-2-(3-moφholin-4-yl-3-oxo-propyl)-phenyl]-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen- 1 -yl]-urea
l-[5-tert-Butyl-2-(moφholine-4-carbonyl)-ρhenyl]-3-[4-(6-moφholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -ylj-urea
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 - yl]-ureido}-phenyl)-acetamide
and the pharmaceutically acceptable derivatives thereof. l-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl J -urea;
l-(3-Methyl-naphthalen-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea;
l-(3-tert-Butyl-phenyl)-3-[4-(4-moφholin-4-ylmethyl-phenyl)-naphthalen-l-yl]-urea;
l-(3-tert-Butyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea;
l-(4-Methyl-biphenyl-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea;
1 -(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - ylj-urea;
l-(5-Chloro-2,4-dimethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
l-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methoxy-3-propyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-moφholin-4-ylmethyl-pyrimidin-5-yl)- naphthalen- 1 -yl] -urea; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-thiomoφholin-4-ylmethyl-phenyl)- naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- l-yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-phenyl)-naphthalen-l- yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[4-(tetiahydro-pyran-4-ylamino)-phenyl]- naphthalen- 1 -yl} -urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(4-methyl-piperazin- 1 -ylmethyl)-pyridin-3- yl J -naphthalen- 1 -yl } -urea;
l-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-amino]-pyridin-3- yl} -naphthalen- 1 -yl)-urea;
1 -(5-tert-Butyl-2-methyl-phenyl)-3 - [4-(4-moφholin-4-ylmethyl-imidazol- 1 -yl)- naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-moφholin-4-ylmethyl-phenyl)-naphthalen-l- yl]-urea;
l-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
l-(5-tert-Butyl-2-methyl-phenyl)-3-{4-[6-(3-methoxy-propylamino)-pyridin-3-yl]- naphthalen- 1 -y 1 } -urea;
l-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-moφholin-4-yl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea; l-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen-l-yl]-urea;
l-(6-tert-Butyl-2-chloro-3-methyl-pyridin-4-yl)-3-[4-(6-thiomoφholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1-yl] -urea;
1 -[2-Methoxy-5 -( 1 -methyl-cyclopropyl)-phenyl] -3 - [4-(2-moφholin-4-ylmethyl- pyrimidin-5-yl)-naρhthalen-l-yl]-urea;
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-3-(3-trifluoromethyl- phenyl)-urea;
l-[4-(6-Mθφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(4-trifluoromethoxy- phenyl)-urea;
l-[5-(l,l-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(4-thiomoφholin-4-ylmethyl- phenyl)-naphthalen- 1 -ylj-urea;
l-[5-(l,l-Dimethyl-propyl)-2-methoxy-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1 -yl] -urea;
l-[5-(l-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(2-moφholin-4-ylmethyl- pyrimidin-5-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-Butyl-2-(lH-pyrazol-4-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
l-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenylJ-3-[4-(5-pyridin-4-ylmethyl-pyridin- 2-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1 -yl] -urea; 1 -[5 -tert-Butyl-2-(3 -moφholin-4-yl-3 -oxo-propyl)-phenyl] -3 - [4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-Butyl-2-(moφholine-4-carbonyl)-phenylJ-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-yl]-urea;
2-[4-tert-Butyl-2-(3-{4-[6-(2,6-dimethyl-moφholin-4-ylmethyl)-pyridin-3-yl]- naphthalen-l-yl}-ureido)-phenoxy]-acetamide;
3-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureidoJ-naphthalen-l-yl}-benzamide;
4-tert-Butyl-2-{3-[4-(2-chloro-4-moφholin-4-ylmethyl-phenyl)-naphthalen-l-ylJ- ureido } -benzamide;
and the pharmaceutically acceptable derivatives thereof.
More preferably the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
l-(2-tert-Butyl-5-methyl-pyridin-4-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(3-tert-Butyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea;
l-(4-Methyl-biphenyl-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea;
l-(4-tert-Butyl-biphenyl-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea;
l-(5-Isopropyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-(5-sec-Butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea; l-(5-tert-Butyl-2-methoxymethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-ρyridin-3-yl)- naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea;
l-(5-tert-Butyl-2-methyl-phenyl)-3-(4-{6-[(3-methoxy-propyl)-methyl-aminoJ-pyridin-3- yl } -naphthalen- 1 -yl)-urea;
l-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methyl-pyridin-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea;
1 -[5 -( 1 , 1 -Dimethyl-propyl)-2-methoxy-phenyl] -3 -[4-(6-moφholin-4-ylmethyl-pyridin-3 - yl)-naphthalen- 1 -ylj-urea;
l-[5-tert-Butyl-2-(lH-pyrazol-4-yl)-phenylJ-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-2-(2-methyl-pyrimidin-5-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-Butyl-2-(3-hydroxy-propyl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1-yl] -urea;
l-[5-tert-Butyl-2-(moφholine-4-carbonyl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-ureido } -phenyl)-acetamide
and the pharmaceutically acceptable derivatives thereof. In another embodiment, the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds:
l-(4-tert-Butyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]- urea;
l-(5-tert-Butyl-2-methyl-phenyl)-3-[4-(4-moφholin-4-ylmethyl-piperidin-l-yl)- naphthalen- 1 -yl] -urea;
l-(6-Chloro-4-trifluoromethyl-pyridin-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(4-Difluoromethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1-yl] -urea;
l-(3-Methyl-naphthalen-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-urea;
1 -[2-Methoxy-5 -( 1 -methyl- 1 -phenyl-ethyl)-phenylj -3-[4-(6-moφholin-4-ylmethyl- ρyridin-3-yl)-naphthalen-l-yl]-urea;
(5-tert-Butyl-2-methyl-phenyl)-carbamic acid 3-(5- {4-[3-(5-tert-butyl-2-methyl-phenyl)- ureido J -naphthalen- 1 -yl } -p yridin-2-ylamino)-propyl ester;
l-(6-tert-Butyl-benzo[l,3]dioxol-5-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 - ylj -ureido} -phenyl)-acetamide;
l,3-Bis-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-Butyl-3-(2,2-dimethyl-[l,3Jdioxolan-4-ylmethyl)-2-hydroxy-phenylJ-3-[4-(6- moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -ylj -urea; 1 -[5-tert-Butyl-2-(2-pyrrolidin- 1 -yl-ethoxy)-phenyl]-3 -[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenyl]-3-[4-(6-moφholin-4- ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-(2,3-Dimethyl-lH-indol-5-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- l-yl]-urea;
l-[4-(6-Mθφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(2-p-tolyloxy-5- tiifluoromethyl-phenyl)-urea;
1 - [2-(2-Methoxy-phenoxy)- 5 -trifluoromethyl-phenyl] -3 - [4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen- 1 -yl]-urea;
1 -[4-(6-Moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -3 -naphthalen- 1 -yl-urea;
l-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-l-ynyl]-plienyl}-3-[4-(6- moφholin-4-ylmethyl-pyridin-3 -yl)-naρhthalen- 1 -yl] -urea;
l-{5-tert-Butyl-2-[3-(tetiahydro-pyran-2-yloxy)-prop-l-ynylJ-phenyl}-3-[4-(6- moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea;
l-(5-HyάrOxymethyl-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea; ,
l-(2-Methoxy-dibenzofuran-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
1 -(2,5-Di-tert-butyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 - ylj-urea;
1 - [3 -(4-Bromo- 1 -methyl- 1 H-pyrazol-3 -yl)-phenyl]-3 - [4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-ylJ-urea; l-(3-Hydroxy-5,6,7,8-tetiahydro-naphthalen-2-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-(l-Acetyl-2,3-dihydro-lH-indol-5-yl)-3-[4-(6-moφholin-4-ylmethyl-ρyridin-3-yl)- naphthalen- 1-yl] -urea;
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(3-oxazol-5-yl-phenyl)- urea;
l-[4-(6-Mθφholin-4-ylmethyl-ρyridin-3-yl)-naphthalen-l-ylJ-3-(3-[l,3,4]oxadiazol-2-yl- phenyl)-urea;
l-(2-Methoxy-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
Furan-2-carboxylic acid (4-tert-butyl-2- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -ureido } -phenyl)-amide;
l-(2-Methoxy-4-phenylamino-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea;
l-(5-Methoxy-2-methyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-ρyridin-3-yl)-naphthalen- 1-yl] -urea;
l-(3-Hydroxy-naphthalen-2-yI)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- l-yl]-urea;
N,N-Diethyl-4-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl] -ureido } -benzenesulfonamide;
l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-[5-(l,l-Dimethyl-propyl)-2-phenoxy-phenyl]-3-[4-(6-moφholin-4-ylmethyl-ρyridin-3- yl)-naphthalen- 1-yl] -urea; l-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin- 3 -yl)-naphthalen- 1 -ylj -urea;
2-Chloro-5-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-ureido}- benzoic acid isopropyl ester;
l-(4-Amino-3,5-dibromo-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-[5-tert-Butyl-3-(3-hydroxy-prop-l-ynyl)-2-methyl-phenylJ-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea;
1 - [5 -tert-Butyl-2-(3 -hydroxy-prop- 1 -ynyl)-phenyl] -3 - [4-(6-moφholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-3-(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-2-methoxy-ρhenyl]-3-[4-(6- moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenyl]-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea;
l-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-[5-(l-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenyl]-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[l,3Jdioxolan-2-yl-pyridin-3-yl)-naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-pyrrolidin-l-yl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea; l-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea;
1 -(5 -tert-Butyl-2-methoxy-phenyl)-3 - [4-(6-hydroxymethyl-pyridin-3 -yl)-naphthalen- 1 - ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-moφholin-4-ylmethyl)- pyridin-3 -yl] -naphthalen- 1 -yl} -urea;
2-(5-tert-Butyl-2-methoxy-phenyl)-N-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -acetamide;
l-(2-Methoxy-5-phenoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indol-7-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-2-cyclopentyloxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- l-yl]-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(3-pyridin-3-yl-pyrrolidin-l-ylmethyl)- pyridin-3 -yl] -naphthalen- 1 -yl } -urea;
l-(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
l-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1 -yl] -urea;
l-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-7-yl)-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea; l-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl]-urea;
l-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-methyl-pyridin-3-yl)-naphthalen-l- yl]-urea;
N- Acetyl-N-(5 -tert-butyl-2-methoxy-3 - {3 - [4-(6-moφholm-4-ylmethyI-pyridin-3 -yl)- naphthalen- 1 -ylj -ureido } -phenyl)-acetamide;
l-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4Joxazin-8-yl)-3-[4-(6- moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl]-urea;
l-[6-tert-Butyl-4-(2-moφholin-4-yl-ethyl)-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8- ylJ-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-imidazol-l-yl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
N-(5-tert-Butyl-2-methoxy-4- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 - yl] -ureido} -phenyl)-methanesulfonamide;
l-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-moφholm-4-ylmethyl-pyridin- 3-yl)-naphthalen- 1 -yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-ureido}-phenyl)-bis(methanesulfon)amide;
l-[5-tert-Butyl-2-(l-methyl-lH-pyrazol-4-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -yl] -urea; l-(2-Methanesulfmyl-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridm-3- yl)-naphthalen- 1 -yl] -urea;
l-(2-Ethanesulfonyl-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1-yl] -urea;
l-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-l-yl]-3-(5- tert-butyl-2-methoxy-phenyl)-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(3-dimethylamino-pyrrolidin>-l -ylmethyl)- pyridin-3 -yl] -naphthalen- 1 -yl } -urea;
N-[l-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-l-yl}-pyridin-2- ylmethyl)-pyrrolidin-3-yl]-acetamide;
l-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-5-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -ylj-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl] -ureido } -phenyι)-propionamide;
l-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(3- trifluoromethanesulfonyl-phenyl)-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-ureido } -phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-ureido}- phenoxy)-acetamide;
l-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-ylJ-urea; l-(6-tert-Butyl-3-cyano-2-methoxymethoxy-pyridin-4-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-(6-tert-Butyl-3-cyano-2-hydroxy-pyridin-4-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-l-yl]-urea;
l-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl]-urea;
1 -[4-(6-Moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -ylj -3 -( 1 ,3,3 -trimethyl-2,3 - dihydro-lH-indol-5-yl)-urea;
l-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-ureido}-phenyl)-benzenesulfonamide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen-l-yl]-ureido}-phenyl)-amide;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(4-moφholin-4-ylmethyl-piperidin-l-yl)- naphthalen- 1 -ylj-urea;
l-[5-tert-Butyl-2-(l-methyl-lH-pyrazol-4-yl)-phenyl]-3-[4-(4-moφholin-4-ylmethyl- piperidin-1 -yl)-naphthalen-l -ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-moφholin-4-ylmethyl-pyrimidin-5-yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen-l-yl]-urea;
l-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen-l-yl]-urea; 2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3- {3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-ureido} -phenyl)-amide;
N-(5- {4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureidoJ-naphthalen- 1 -yl} -pyrazin-2-yl)- methanesulfonamide;
l-[4-(6-{[Bis-(2-cyano-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-l-yl]-3-(5-tert- butyl-2-methoxy-phenyl)-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(4-methyl-piperazin- 1 -ylmethyl)-pyridin-3 - yl] -naphthalen- 1 -yl} -urea;
1 -(5 -tert-Butyl-2-methoxy-phenyl)-3 - [4-(6-thiomoφholin-4-ylmethyl-pyridin-3 -yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-l-ylmethyl)-pyridin- 3 -yl] -naphthalen- 1 -yl } -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(l-oxo-tetrahydro-thiopyran-4-ylamino)- pyridin-3-yl]-naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetiahydro-pyran-4-ylamino)-pyridin-3-yl]- naphthalen- 1 -yl } -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetiahydro-furan-2- ylmethyl)-amino] -methyl } -pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-moφholin-4-ylmethyl)- pyridin-3 -yl] -naphthalen- 1 -yl } -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-moφholin-4-yl-ethylamino)-methyl]- pyridin-3-yl}-naphthalen-l-yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methyl-3-oxo-piperazin-l-ylmethyl)- pyridin-3-ylJ-naphthalen- 1 -yl} -urea; l-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-l-yl}-pyridin-2- ylmethyl)-piperidine-3 -carboxylic acid amide;
l-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureidoJ-naphthalen-l-yl}-pyridin-2- ylmethyl)-piperidine-4-carboxylic acid amide;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(l-oxo-114-thiomoφholin-4-ylmethyl)- pyridin-3 -ylj -naphthalen- 1 -yl } -urea;
l-(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indol-5-yl)-3-[4-(6-moφholin~4-ylmethyl- pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
1 -(5 -tert-Butyl-2-methoxy-phenyl)-3 - {4- [6-(3 -oxo-piperazin- 1 -ylmethyl)-pyridin-3 -yl] - naphthalen- 1 -yl } -urea;
1 - {4-[6-(4- Acetyl -piperazin- 1 -ylmethyl)-pyridin-3-yl] -naphthalen- 1 -yl } -3 -(5 -tert-butyl- 2-methoxy-phenyl)-urea;
4-(5- {4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen- 1 -yl} -pyridin-2- ylmethyl)-piperazine-l -carboxylic acid ethyl ester;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-pyridin-3-yl-ethylamino)-methyl]- pyridin-3 -yl } -naphthalen- 1 -yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetiahydro-furan-3-ylamino)-methylJ- pyridin-3-yl}-naphthalen-l-yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-aminoJ- methyl} -pyridin-3 -yl)-naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-methylsulfanyl-ethylamino)-methyl]- pyridin-3 -yl } -naphthalen- 1 -yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-oxa-5-aza-bicyclo[2.2.1]hept-5-ylmethyl)- ρyridin-3 -yl] -naphthalen- 1 -yl } -urea; l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-moφholin-4-ylmethyl)- pyridin-3 -yl]-naphthalen- 1 -yl } -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(2-piperazin-l-yl-ethylamino)-methyl]- pyridin-3-yl} -naphthalen- l-yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyrimidin-2-yl-piperazin-l-ylmethyl)- pyridin-3 -yl J -naphthalen- 1 -yl } -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-pyridin-2-yl-piperazin-l-ylmethyl)- pyridin-3 -ylj -naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-l- ylmethylJ-pyridin-3-yl}-naphthalen-l-yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(moφholine-4-carbonyl)-pyridin-3-yl]- naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-thia-5-aza-bicyclo[2.2.1Jhept-5-ylmethyl)- pyridin-3-ylJ-naphthalen-l-yl}-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-moφholin-4-ylmethyl-pyrazin-2-yl)- naphthalen- 1 -yl] -urea;
l-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yl)-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea;
l-(3-Amino-5-tert-butyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
N-(5- {4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen- 1 -yl} -pyridin-2-yl)- acetamide;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-ρyridin-3-yl)-naphthalen-l- yl]-ureido} -phenyl)-N-methyl-acetamide; N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-ureido}-phenyl)-2,2,2-trifluoro-acetamide;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-ylJ-naphthalen-l- yl}-urea;
1 -(5 -tert-Butyl-2-methoxy-phenyl)-3 - {4- [6-(pyridin-3 -ylamino)-pyridin-3 -yl] - naphthalen- 1 -yl } -urea;
[4-(6-Mθφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-carbamic acid 3-tert-butyl- phenyl ester;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylJ-ureido}-phenyl)-methanesulfonamide and
and the pharmaceutically acceptable derivatives thereof.
In another preferred embodiment the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is selected from the following compounds :
l-(3-Methyl-naphthalen-2-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylj-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylJ-ureido}-phenyl)-acetamide;
l-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-hydroxy-phenylJ-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-ylJ-urea;
l-(2,3-Dimethyl-lH-indol-5-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- l-yl]-urea;
l-{5-tert-Butyl-2-methyl-3-[3-(tetrahydro-pyran-2-yloxy)-prop-l-ynyl]-phenyl}-3-[4-(6- moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea; l-(2-Methoxy-5-tiifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-[5-(2,2-Dimethyl-propionyl)-2-methyl-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin- 3-yl)-naphthalen-l-yl]-urea;
l-[5-tert-Butyl-3-(3-hydroxy-prop-l-ynyl)-2-methyl-phenylJ-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea;
l-[5-tert-Butyl-2-(3-hydroxy-prop-l-ynyl)-phenylJ-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen- 1 -yl]-urea;
l-[5-tert-Butyl-3-(2,2-dimethyl-[l,3]dioxolan-4-ylmethyl)-2-methoxy-phenylJ-3-[4-(6- moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -ylj -urea;
l-[5-tert-Butyl-3-(2,3-dihydroxy-propyl)-2-methoxy-phenylJ-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen- 1 -ylj-urea;
l-(5-tert-Butoxy-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea;
l-[5-(l-Cyano-cyclopropyl)-2-methoxy-phenyl]-3-[4-(6-moφholin-4-ylmethyl-pyridin- 3 -yl)-naphthalen- 1 -ylj -urea;
l-[5-tert-Butyl-3-(2-diethylamino-ethyl)-2-methoxy-phenylJ-3-[4-(6-moφholin-4- ylmethyl-pvridin-3-yl)-naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-[l,3Jdioxolan-2-yl-pyridin-3-yl)-naphthalen- 1 -ylj-urea;
1 -(5-tert-Butyl-2-pyrrolidin- 1 -yl-phenyl)-3 - [4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-dimethylamino-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- l-yl]-urea; l-(5-tert-Butyl-2-propoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-hydroxymethyl-pyridin-3-yl)-naphthalen-l- ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-moφholin-4-ylmethyl)- pyridin-3 -yl J-naphthalen- 1 -yl } -urea;
1 -(5-Cyclohexyl-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -urea;
l-(2,4-Dimethoxy-5-trifluoromethyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
1 -(3 - Amino-5-tert-butyl-2-methoxy-phenyl)-3 -[4-(6-methyl-pyridin-3 -yl)-naphthalen- 1 - ylj-urea;
N-Acetyl-N-(5-tert-butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj -ureido } -phenyl)-acetamide;
l-(6-tert-Butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo[l,4]oxazin-8-yl)-3-[4-(6- moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-ethoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-isopropoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-(5-tert-Butyl-2-imidazol-l-yl-phenyl)-3-[4-(6-moφholm-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea; l-(5-tert-Butyl-3-ethylamino-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin- 3-yl)-naphthalen- 1 -ylj-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-ureido} -phenyl)-bis(methanesulfon)amide;
l-[5-tert-Butyl-2-(l-methyl-lH-pyrazol-4-yl)-phenyl]-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen- 1 -yl]-urea;
1 -(2-Methanesulfinyl-5-trifluoromethyl-ρhenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1 -yl] -urea;
l-[4-(6-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-pyridin-3-yl)-naphthalen-l-yl]-3-(5- tert-butyl-2-methoxy-phenyl)-urea;
N-[l-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-l-yl}-pyridin-2- ylmethyl)-pyrrolidin-3-yl]-acetamide;
l-(l-Acetyl-3,3-dimethyl-2,3-dihydro-lH-indol-5-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3 -yl)-naphthal en- 1 -yl]-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl J -ureido } -phenyl)-propionamide;
l-(5-tert-Butyl-2-methyl-benzooxazol-7-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
l-[4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-3-(3- trifluoromethanesulfonyl-phenyl)-urea; f.
•i N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφhohn-4-ylmethyl-pyridin-3-yl)-naphthalen-l- yl]-ureido}-phenyl)-isobutyramide;
2-(4-tert-Butyl-2-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-ureido}- phenoxy)-acetamide; l-(5-tert-Butyl-2-oxo-2,3-dihydro-benzooxazol-7-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen- 1 -yl]-urea;
l-(5-tert-Butyl-3-cyano-2-methoxy-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea;
l-(5-tert-Butyl-benzooxazol-7-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
N-(5-tert-Butyl-2-methoxy-3-{3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l- ylJ-ureido}-phenyl)-benzenesulfonamide;
Ethanesulfonic acid (5-tert-butyl-2-methoxy-3- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3- yl)-naphthalen- 1 -yl] -ureido} -phenyl)-amide;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-moφholin-4-ylmethyl-pyrimidin-5-yl)- naphthalen- 1 -ylj -urea;
l-(5-tert-Butyl-2-methylsulfanyl-phenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1-yl] -urea;
l-(5-tert-Butyl-2-methoxy-pyridin-3-yl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl] -urea;
2,2,2-Trifluoro-ethanesulfonic acid (5-tert-butyl-2-methoxy-3-{3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l -yl]-ureido} -phenyl)-amide;
N-(5-{4-[3-(5-tert-Butyl-2-methyl-phenyl)-ureidoJ-naphthalen-l-yl}-pyrazin-2-yl)- methanesulfonamide;
l-[4-(6-{[Bis-(2-cyano-ethyl)-aminoJ-methyl}-pyridin-3-yl)-naphthalen-l-ylJ-3-(5-tert- butyl-2-methoxy-phenyl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(4-methyl-piperazin-l-ylmethyl)-pyridin-3- ylj-naphthalen-l-yl}-urea; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-thiomoφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -ylj-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-piperidin-l-ylmethyl)-pyridin- 3-yl]-naphthalen-l-yl}-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(l-oxo-tetiahydro-thiopyran-4-ylamino)- pyridin-3 -yl] -naphthalen- 1 -yl } -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(tetrahydro-pyran-4-ylamino)-pyridin-3-ylJ- naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-(tetiahydro-furan-2- ylmethyl)-amino] -methyl } -pyridin-3 -yl)-naphthalen- 1 -ylj -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2-methoxymethyl-moφholin-4-ylmethyl)- pyridin-3 -yl] -naphthalen- 1 -yl } -urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(2-methyl-3-oxo-piperazin- 1 -ylmethyl)- pyridin-3-yl]-naphthalen-l-yl}-urea;
l-(5-{4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen-l-yl}-pyridin-2- ylmethyl)-piperidine-3-carboxylic acid amide;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3 - {4-[6-( 1 -oxo- 114-thiomoφholm-4-ylmethyl)- pyridin-3 -yl J -naphthal en- 1 -yl } -urea;
l-(3,3-Dimethyl-2-oxo-2,3-dihydro-lH-indol-5-yl)-3-[4-(6-moφholin-4-ylmethyl- pyridin-3-yl)-naphthalen-l-ylj-urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(3-oxo-piperazin- 1 -ylmethyl)-pyridin-3-ylJ- naphthalen-l-yl}-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[(tetiahydro-furan-3-ylamino)-methyl]- pyridin-3 -yl} -naphthalen- 1 -yl)-urea; l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(6-{[(2-cyano-ethyl)-pyridin-3-ylmethyl-amino]- methyl } -pyridin-3 -yl)-naphthalen- 1 -yl] -urea;
1 -(5-tert-Butyl-2-methoxy-phenyl)-3- {4-[6-(2-oxa-5-aza-bicyclo[2.2.1 ]hept-5-ylmethyl)- pyridin-3 -yl] -naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(2,6-dimethyl-moφholin-4-ylmethyl)- pyridin-3-yl]-naphthalen-l-yl}-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-(4-{6-[4-(3-methoxy-phenyl)-piperazin-l- ylmethyl]-pyridin-3-yl}-naphthalen-l-yl)-urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(moφholine-4-carbonyl)-pyridin-3-yl]- naphthalen- 1 -yl} -urea;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(5-moφholin-4-ylmethyl-pyrazin-2-yl)- naphthalen- 1 -yl]-urea;
l-(6-tert-Butyl-3-oxo-3,4-dihydro-2H-benzo[l,4Joxazin-8-yl)-3-[4-(6-moφholin-4- ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-urea;
l-(3-Amino-5-tert-butyl-2-methoxy-ρhenyl)-3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)- naphthalen- 1 -yl]-urea;
N-(5- {4-[3-(5-tert-Butyl-2-methoxy-phenyl)-ureido]-naphthalen- 1 -yl} -pyridin-2-yl)- acetamide;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 - ylJ-ureido}-phenyl)-N-methyl-acetamide;
N-(5-tert-Butyl-2-methoxy-3- {3-[4-(6-moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen- 1 - ylj -ureido } -phenyl)-2,2,2-trifluoro-acetamide;
l-(5-tert-Butyl-2-methoxy-phenyl)-3-{4-[6-(pyridin-3-yloxy)-pyridin-3-yl]-naphthalen-l- yl}-urea; [4-(6-Moφholin-4-ylmethyl-pyridin-3-yl)-naphthalen-l-yl]-carbamic acid 3-tert-butyl- phenyl ester;
N-(5-tert-Butyl-2-methoxy-3 - { 3 - [4-(6-moφholin-4-ylmethyl-pyridin-3 -yl)-naphthalen- 1 - ylj -ureido }-phenyl)-methanesulfonamide and
and the pharmaceutically acceptable derivatives thereof.
Particularily preferred the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is:
and
or the pharmaceutically acceptable salts thereof.
More particularily preferred the invention relates to pharmaceutical combinations comprising A and B, wherein the p38 kinase inhibitor B is:
and the pharmaceutically acceptable salts thereof.
Of particular importance according to the invention are the abovementioned pharmaceutical combinations comprising A and B, for use as pharmaceutical compositions with an anti-cytokine activity.
The invention also relates combinations comprising A and B, for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine mediated disease or condition..
The invention also relates to pharmaceutical preparations, containing as active substance one or more compounds combinations comprising A and B, or the pharmaceutically acceptable derivatives thereof, optionally combined with conventional excipients and/or carriers.
Any reference to the abovementioned p38 kinase inhibitors include "pharmaceutically acceptable derivative" thereof which refers to any pharmaceutically acceptable salt or ester of a compound of this invention, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound B of this invention, a pharmacologically active metabolite or pharmacologically active residue thereof. A pharmacologically active metabolite shall be understood to mean any compound B of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative p 38 compounds. Pharmaceutically acceptable salts of the compounds of this invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitiic, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts. Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C1- C4 alkyl)4+ salts.
In addition, the compounds of this invention include prodrugs of p38 compounds. Prodrugs include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug of this invention is administered to a patient, the prodrug may be transformed into a compound B of the invention, thereby imparting the desired pharmacological effect.
For therapeutic use, the pharmaceutical combinations of A and B according to the invention may be administered in any conventional dosage form in any conventional manner. Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation.
The preferred modes of administration are oral, topical or intravenous.
The the pharmaceutical combinations of A and B according to the invention may be administered separately, or in a combination formulation with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutical compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients. Advantageously, such combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as mono therapies. Pharmaceutical combinations of A and B may therefore be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Reference is this regard may be made to Cappola et al.: US patent application no. 09/902,822, PCT/US 01/21860 and US provisional application no. 60/313,527, each incoφorated by reference herein in their entirety. The optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art.
As mentioned above, dosage forms of the compositions described herein include pharaiaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art. These carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances. Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. Regarding p38 component B, in some embodiments, dosage levels range from about 1- 1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required.
Reference in this regard may also be made to US provisional application no. 60/339,249. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician. In another aspect the present invention relates to a pharmaceutical composition suitable for inhalation which contains one or more salts A and one or more compounds B, optionally in the form of their solvates or hydrates. The active substances may either be combined in a single preparation or contained in two separate formulations. Pharmaceutical compositions which contain the active substances A and B in a single preparation are preferred according to the invention.
The present invention also relates to the use of A and B for preparing a pharmaceutical combinations containing therapeutically effective quantities of A and B for treating cytokine mediated diseases, provided that tieatment with p38 kinase inhibitors is not contiaindicated from a therapeutic point of view, by simultaneous or successive administration.
In the active substance combinations of A and B according to the invention, ingredients A and B may be present in the form of their enantiomers, mixtures of enantiomers or in the form of racemates.
The proportions in which the two active substances A and B may be used in the active substance combinations according to the invention are variable. Active substances A and B may possibly be present in the form of their solvates or hydrates. Depending on the choice of the compounds A and B, the weight ratios which may be used within the scope of the present invention vary on the basis of the different molecular weights of the various compounds and their different potencies. Determination of ratios by weight is dependent on particular active ingredients of A and B, and within the skill in the art.
The active substance combinations of A and B according to the invention may be administered by inhalation or by nasal application. For this puφose, ingredients A and B have to be made available in inhalable forms. Inhalable preparations include inhalable powders, propellant-containing metering aerosols or propellant-free inhalable solutions. Inhalable powders according to the invention containing the combination of active substances A and B may consist of the active substances on their own or of a mixture of the active substances with physiologically acceptable excipients. Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile inhalable solutions ready for use. The preparations according to the invention may contain the combination of active substances A and B either together in one formulation or in two separate formulations. These formulations which may be used within the scope of the present invention are described in more detail in the next part of the specification.
The Examples which follow serve to illustrate the present mvention in more detail without restiicting the scope of the invention to the following embodiments by way of example.
Starting materials
Component B, p38 inhibitor: BIRB 796 BS l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-yl]-3-[4-(2-moφholin-4-yl-ethoxy)naphthalen-l- yl]-urea.
The above p38 component B used in the following examples, may be obtained as described in US patent no. 6,319,921 or US application serial no. 09/611 , 109.
5-Amino-3-t-butyl-l-p-tolylpyrazole hydrochloride: A solution of pivaloylacetonitrile (750 g, 6.0 mol) and p-tolylhydrazine hydrochloride (660 g, 4.2 mol) in methanol (2.8 L) was refluxed for 3 h. Heptane was added, and methanol was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 1.05 kg, 94%. ^CDCl H NMR 3) 7.50 (d, 2H), 7.30 (d, 2H), 5.60 (s, IH), 2.45 (s, 3H), 1.40 (s, 9H). MS (CI) m/z 229 (M+ + H).
5-(2,2,2-Trichloroethoxycarbonyl)amino-3-t-butyl-l-p-tolylpyrazole: A mixture of 5- amino-3-t-butyl-l-p-tolylpyrazole hydrochloride (300 g, 1.13 mol), water (0.9 L), EtOAc (2.1 L) and NaOH (117 g, 2.84 mol) was stirred between 5 -15 °C for 30 min. To this mixture, 2,2,2-trichloroethyl chloroformate (342 g, 1.58 mol) was added over 1 h between 5 - 15 °C. The mixture was stirred at room temperature for 2 h, and then the aqueous layer was separated from the EtOAc layer. The EtOAc layer was washed with brine (2 x 0.9 L) and dried over MgSO (60 g). The EtOAc layer was collected by filtration. To this solution, heptane was added. A part of the solution was removed by distillation. The product was crystallized from the solution, collected by filtration and dried in vacuum oven to constant weight. Yield: 409 g, 90%. 1H NMR (CDC13 7.40 (d, 2H), 7.30 (d, 2H), 6.40δ) (s, IH), 4.80 (s, 2H), 2.40 (s, 3H), 1.40 (s, 9H). MS (El) m/z 404 (M+).
4-Nitro- 1 -(2-moφholinethoxy)naphthalene: A mixture of 4-nitto-l-hydroxynaphthalene (194 g, 1.0 mol), 4-(2-chloroethyl)moφholine hydrochloride (264 g, 1.4 mol), NaOH (58 g, 1.4 mol), K2CO3 (339 g, 2.4 mol) and l-methyl-2-pyrrolidinone (1.0 L) was heated to 90 - 100 °C and held for 1 - 2 h. The mixture was cooled to 40 °C and water was slowly added. The mixture was cooled to 5 °C and held for 4 h. The product was collected by filtration, washed with water, cyclohexane and dried in vacuum to constant weight. Yield: 227 g, 75%. 1H NMR (CDC13) 8.76 (d, IH), 8.38 (m, 2H), 7.74 (dd, IH), 7.58 (dd, 1 H), 6.79 (d, 1 H), 4.38 (dd, 2 H), 3.74 (d, 4 H), 2.98 (dd, 2H), 2.65 (d, 4 H). MS (El) m/z 303 (M + 1).
4- Amino- 1 -(2-moφholinethoxy naphthalene hydrochloride: A mixture of 4-nitio- 1 -(2- moφholinethoxy)naρhthalene (40 g, 0.13 mol), MeOH (280 mL) and Pd/C (50% water, 1.2 g) was hydrogenated under 30 psi for 24 h. The catalyst was filtered through a layer of diatomaceous earth under nitrogen. To this filtrate 20 mL of HCI (37%) and cyclohexane (200 mL) were added. The solvent was removed under reduced pressure and the product collected by filtration. The product was dried in vacuum to constant weight. Yield: 33 g, 82%. 1H NMR (DMSO) 8.38 (d, IH), 8.00 (d, IH), 7.72 (dd, IH), 7.64 (m, 2H), 7.05 (d, IH), 4.62 (s, 2H), 4.00 (b, 4H), 3.88 (s, 2H), 3.40 (b, 4H). MS (El) m z 273 (M+).
l-[3-tert-butyl-l-p-tolyl-lH-pyrazol-5-ylJ-3-[4-(2-moφholin-4-yl-ethoxy naphthalen-l- yl]-urea: A solution of 5 -(2,2,2-trichloroethoxycarbonyl)amino-3 -t-butyl- 1 -p- tolylpyrazole ( 10.6 g, 26 mmol), 4-amino-l-(2-moφholinethoxy)naphthalene (free base from HCI salt above, 7.16 g, 26 mmol), diisopropylethylamine (3.2 g, 25 mmol) and DMSO (75 mL) was heated to 55 - 60 °C and held for 1.5 h. To this solution, ethyl acetate (100 mL) was added. The organic layer was washed with brine (4x50 mL), and dried over MgSO4. The solvent was removed under reduced pressure, and residue was crystallized from acetonitrile (50 mL) at 0 °C. The product was collected by filtration, recrystallized from isopropanol and dried in vacuum to constant weight, m.p.: 151-152 °C. Yield: 11.4g, 87%. J 8.75 (s, lH),δH NMR (DMSO) 8.51 (s, IH), 8.21 (d, IH), 7.85 (d, IH), 7.65 (d, IH), 7.55 (m, 2H), 7.49 (dd, IH), 7.35 (dd, IH), 6.95 (d, IH), 6.38 (s, IH), 4.26 (dd, 2H), 3.60 (dd, 4H), 2.81 (dd, 2H), 2.55 (dd, 4H), 2.38 (s, 3H), 1.29 (s, 9H). MS (CI) m/z 528 (M++l).
FORMULATIONS
In order to prepare the oral dosage formulations for use in tablets, the formulation described in 09/902,822 or PCT US 01/21860 may be used; for parental administration formulations, see US application no. 10/214,782.
Table 1
Core Tablet Formulas for 20, 25, 50, 100 and 200 mg Core Tablets
Examples of Pharmaceutical Combinations
1)
2)
3)
Other formulations comprising particular active ingredients of A and B can be obtained based on the teachings and the examples provided herein, and from materials and methods known in the art without undue experimentation. These variations are within the scope of the invention.
Methods of Therapeutic Use
Combinations of p38 Compounds with Other Compounds in Psoriasis
In psoriasis, known combination treatments have been effective and are used as rotation therapy for maintenance of remission or to combination tieatments if refractory to usual systemic products. Most of the combinations are with different modes of action either to improve efficacy or to reduce side effects by reduction of the dosage. See Van de Kerkhof, P. 1997 Clinics in Dermatology, 15:831-834, which showed the interest of topical steroids or Vitamin D with systemic agents.
Few systemic agents have been properly tested in clinical trials but two combinations are widely accepted are ultraviolet B (UVB) or psoralens ultraviolet A (PUVA) plus retinoi'ds; or methotrexate or cyclosporin + retinoϊds.
A preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with immunotherapy drugs which include cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti-CD25, peptide T, LFA3TIP, DAB38 , CTLA-4Ig, E-selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed Griffiths, Christopher EM, 1998 Hospital Medicine, Vol 59 No 7, and the obvious variants thereof.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with methotrexate (MTX). It is expected this combination to be effective because of good tolerability of MTX on the short term and of acceptability if maintenance of remission is obtained with good quality of life.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with cyclosporine especially because of cyclosporine efficiency for induction of remission. Another embodiment of the invention comprises administration in the following sequence: induction with BIRB 796 BS + cyclosporine, followed by continuation with BIRB 796 BS after decrease of dosing and discontinuation of cyclosporine.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with retinoϊds. Retinoids provide minimal efficacy with potential Cyt P450 interactions and risk of teratogenicity, this would be alleviated by continuation therapy with BIRB 796 BS.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with topical active ingredijgnts A chosen from glucocorticoids, vitamin D derivatives, topical retinoϊds and dithianol. A more preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, is with vitamin D derivatives, most preferred within this list is BIRB796 with calcipotriol or with tacalcitol.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with macrolids preferably with ascomycin analogues topically, more preferentially with those available as well orally such as pimecrolimus.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with cell adhesion molecules inhibitors: anti LFA3, anti LFA1. This includes adhesion molecule blockage by recombinant fusion protein like alefacept anti LFA3-IgCl or by anti-CD 11 monoclonal antibodies efalizumab, and the obvious variants thereof. Cell adhesion molecules inhibitors appear to provide an acceptable response rate with limited tolerability problems. Combination with a p38 inhibitor such as BIRB 796 could avoid the disadvantage of their injectable form, with CAM inhibitors being used intermittently. Another embodiment of the invention comprises administration in the following sequence: induce with BIRB 796 BS + CAM inhibitors then maintain the treatment with BIRB 796 BS alone + retreatment with CAM inhibitors in case of significant relapse.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with another anti-TNFα active ingredient. A preferred embodiment is wherein the other anti-TNFα active ingredient is chosen from infliximab or etanercept, preferably infliximab. Infliximab appears seems to have a higher rate of response for induction of remission which recently was said to be maintained on the long term. Within the scope of the invention is the use of topical or general antisens inhibitors of TNF α such as ICAM-1 ISIS 2302 in combination with a p38 inhibitor compound, preferably BIRB 796 BS.
Another preferred combination for treating psoriasis is a p38 inhibitor compound, preferably BIRB 796 BS, with anti-CD4, anti CD80 (IDEC-114 or ABX-IL8), DAB IL-2, DAB38 IL-2, CTLA4Ig, IL10, the IL2 receptor inhibitors such as daclizumab (anti- TAC), basiliximab. See Tutione, W.D., November 2001, Biologic Therapy for Psoriasis vol 68; Tutione, W.D.,December 2001, Biologic Therapy for Psoriasis vol 68; Ben- Bassat, H. 2001 Current Opinion in hivestigational Drugs Vol 2 No 11; Salim, A. et al, 2001 Current Opinion in Investigational Drugs Vol 2 No 11.
ANIMAL MODELS :
Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art. Reference in this regard may be made to: Schon, Michael P. April 1999 Animal models of Psoriasis - What can we learn from them, The Society for Investigative Dermatology - Reviews, Vol 112. No. 4,405-410.
Combinations of p38 Compounds with Other Compounds in Rheumatoid Arthritis:
In Rheumatoid Arthritis, combination of immunosuppressive or immunomodulatory agents is a long and well established therapeutic paradigm. Combination partners recruit from various therapeutic entities. Their identification is either based on empirical data supported by evolving knowledge about the underlying mechanisms or based on a well defined mode of action. These agents are generally addressed to be Disease Modifying Antirheumatic Drugs (DMARDs) or Slow Acting Antirheumatic Drugs (SAARDs). Apart from the combinations listed below, combination of a ρ38 compound, preferably BIRB 796 BS, with one or more agents classified as DMARD/SAARD or NSAID and/or corticosteroid, fall under this invention. A preferred combination for treating rheumatoid arthritis is a p38 inhibitor compound, preferably BIRB 796 BS, with one or more of the following immunosuppressive, immunomodulatory, or cytostatic drugs including hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate , azathioprine and cyclophosphamide.
Another preferred combination for treating rheumatoid arthritis is a p38 inhibitor compound, preferably BIRB 796 BS, with angiogenesis inhibitors such as compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta-IB and alpha- interferon.
Another preferred combination for treating rheumatoid arthritis is a p38 inhibitor compound, preferably BIRB 796 BS, with cell adhesion like LFA-1 or ICAM-1.
A more preferred combination for treating rheumatoid arthritis is a p38 inhibitor compound, preferably BIRB 796 BS, with anti-TNF antibodies or TNF-receptor antagonists such as Etanercept, infliximab, Adalimumab (D2E7), CDP 571, and Ro 45- 2081 (Lenercept), or biologic agents directed against targets like CD-4, CTLA-4, LFA-1, IL-6, IC AM- 1 , and C5.In another embodiment BIRB 796 BS is combined with Infliximab and Methotrexate.
Another preferred combination for treating rheumatoid arthritis is a p38 inhibitor compound, preferably BIRB 796 BS, with IL-1 receptor antagonists, such as Kineret.
Another preferred combination for treating rheumatoid arthritis is a p38 inhibitor compound, preferably BIRB 796 BS, with non-steroid anti-inflammatory drags (NS AIDs) including acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, caφrofen, indoprofen, ketorolac tiomethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tomietin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide, and the like.
Another preferred combination for treating rheumatoid arthritis is a p38 inhibitor compound, preferably BIRB 796 BS, with glucocorticosteroids such as betamethasone, dexamethasone, methylprednisolone, prednisolone , and deflazacort.
Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art. Reference in this regard may be made to: Wooley, P. H. 1998, Animal models of arthritis. In Klippel J.H., Dieppe, P. A., (eds.) Rheumatology, second edition, 5.8.1-5.8.6. Mosby, London, Philadelphia, St. Louis, Sydney, Tokio.
Combinations of p38 Compounds with Other Compounds in Crohn's disease:
In Crohn's disease, the following groups of drugs combined with a p38 inhibitor may be effective: steroids/budesonide, 5-ASA drugs like mesalasine, immunosuppressants, biological agents and adhesion molecule inhibitors.
A preferred combination for treating Crohn's disease is a p38 inhibitor compound, preferably BIRB 796 BS, with one or more of the following: steroids include all those listed herein above, 5-ASA, Methotrexate and Azathioprine.
Another preferred combination for treating Crohn's disease is a p38 inhibitor compound, preferably BIRB 796 BS, with IL-1 receptor antagonists, such as Kineret.
Another preferred combination for treating Crohn's disease is a p38 inhibitor compound, preferably BIRB 796 BS, with anti-TNF antibodies or TNF-receptor antagonists such as Etanercept, Infliximab, Adalimumab (D2E7), CDP 571, andRo 45-2081 (Lenercept), or biologic agents directed against targets like CD-4, CTLA-4, LFA-1, IL-6, ICAM-1, and C5. In another embodiment BIRB 796 BS is combined with Infliximab and Methotrexate. Preferred is BIRB 796 BS is combined infliximab. Another preferred combination for treating Crohn's disease is a p38 inhibitor compound, preferably BIRB 796 BS, with IL-10, ISIS 8 (anti ICAM 1), Antegren (VCAM receptor antagonist).
Another preferred combination for treating Crohn's disease is a p38 inhibitor compound, preferably BIRB 796 BS, with any of the compounds disclosed in US Pat. No. 6,492,408, more preferably:
Another preferred combination for treating Crohn's disease is ap38 inhibitor compound, preferably BIRB 796 BS, with an antiviral such as any of the compounds disclosed in WO 00/59929, more preferably compound number 822, exemplified in example 34C:
Any of the above mentioned combinations within the scope of the invention may be tested by animal models known in the art.
All references cited in this application are incoφorated by reference herein in their entirety.

Claims

WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising one or more active ingredients A together with one or more p38 kinase inhibitor B, optionally combined with conventional excipients and/or carriers, wherein A is chosen from one or more
NSAIDs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, angiogenesis inhibitors, biological agents, steroids, vitamin D3 analogs, retinoinds and inhibitors of cell adhesion molecules chosen from LFA-1 and ICAM-1; and wherein B is chosen from
šnd
or the pharmaceutically acceptable salts thereof.
2. A pharmaceutical composition comprising an active ingredients A together with one or more p38 kinase inhibitor B, optionally combined with conventional excipients and/or carriers, wherein A is chosen from budesonide, Vitamin D, 5-ASA drugs, glucocorticosteroids glucocorticosteroids chosen from betamethasone, dexamethasone, methylprednisolone, prednisolone and deflazacort, retinoids, methotrexate, pimecrolimus, tacrolimus, ascomycine, daclizumab, anti-CD4, anti CD80, anti-CD25, peptide T, LFA3TIP, DAB389, anti LFA3-IgCl, CTLA-4Ig, E- selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, macrolids, ICAM-1 ISIS 2302 , ISIS 8 (anti ICAM 1),DAB IL-2, DAB389 IL-2, basiliximab, hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, leflunomide, cyclophosphamide, compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha-interferon, Adalimumab (D2E7), CDP 571, and Ro 45-2081 (Lenercept), with IL-1 receptor antagonists, NSAIDs chosen from acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, caφrofen, indoprofen, ketorolac tiomethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid, flosulide,
and wherein B is chosen from
and
or the pharmaceutically acceptable salts thereof.
3. The compositions according to claims 1 or 2 wherein B is
4. The composition according to claim 1 wherein A is chosen from methotiexate, infliximab, leflunomide and combinations thereof, and B is
5. A pharmaceutical composition comprising BIRB 796 BS, Lactose Monohydrate, Povidone K30, Microcrystalline Cellulose, Pregelatinized Starch, Sodium Starch Glycolate, Colloidal Silicon Dioxide and Magnesium Stearate, wherein the amount of each is chosen from:
6. The pharmaceutical composition according to claim 5 further comprising one or more second active ingredients chosen from:
NS AIDs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, angiogenesis inhibitors, biological agents, steroids, vitamin D3 analogs, retinoinds and inhibitors of cell adhesion molecules chosen from LFA-1 and ICAM-1.
7. Use of one or more active ingredients A together with one or more p38 kinase inhibitor B, according to claim 1, for the manufacture of preparing a pharmaceutical composition which is-suitable-for the treatmentiag of a cytokine mediated disease.
8. Use of one or more active ingredient A together with one or more p38 kinase inhibitor B, optionally combined with conventional excipients and/or carriers, for the tieatingment of rheumatoid arthritis, wherein A is chosen from one or more
NSAIDs, immunosuppressive drugs, immunomodulatory drugs, cytostatic drugs, angiogenesis inhibitors, biological agents, glucocorticosteroids and inhibitors of cell adhesion molecules chosen from LFA-1 and ICAM-1; and wherein B is chosen from
and
or the pharmaceutically acceptable salts thereof.
9. The use according to claim 8 wherein
wherein A is chosen from one or more hydroxychloroquine, D-penicillamine, sulfasalazine, auranofin, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotiexate, azathioprine and cyclophosphamide; the angiogenesis inhibitors are chosen from compounds directed against VEGF, taxol, pentoxyfylline, thalidomide, interferon beta- IB and alpha-interferon; the biological agents are chosen from etanercept, infliximab, adalimumab (D2E7), CDP 571, Ro 45-2081 (Lenercept), biologic agents directed against CD-4, CTLA-4, LFA-1, IL-6, ICAM-1 or C5 and IL-1 receptor antagonists; the NSAIDs are chosen from acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, indomethacin, ketoprofen, caφrofen, indoprofen, ketorolac tiomethamine, magnesium salicylate, meclofenamate sodium, mefenamic acid, oxaprozin, piroxicam, sodium salicylate, sulindac, tolmetin, meloxicam, rofecoxib, celecoxib, etoricoxib, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, remifenzone, salsalate, tiaprofenic acid and flosulide; the glucocorticosteroids are chosen from betamethasone, dexamethasone, methylprednisolone, prednisolone and deflazacort.
10. The use according to claim 9 wherein B is
11. The use according to claim 10 wherein A is infliximab alone or combined with methotrexate.
12. Use of one or more active ingredient A together with one or more p38 kinase inhibitor B, optionally combined with conventional excipients and/or carriers, for the manufacture of-preparing a pharmaceutical composition which is suitablc-for the tieatment ofmg- psoriasis wherein A is chosen from one or more retinoids, immunosuppressive drugs, immunomodulatory drugs, biological agents, steroids, Vitamin D analogs and inhibitors of cell adhesion molecules, or A is a therapy chosen from ultraviolet B (UVB), psoralens ultiaviolet A (PUVA) each optionally administered with retinoids, methotiexate or cyclosporin + retinoids; and wherein B is chosen from
and
or the pharmaceutically acceptable salts thereof.
13. The use according to claim 12, wherein wherein A is chosen from one or more cyclosporin, pimecrolimus, tacrolimus, ascomycine, anti-CD4, anti CD80, anti-CD25, peptide T, LFA3TIP, anti LFA3-IgCl, anti-CDll, DAB389, CTLA-4Ig, E-selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, methoxtiexate, retinoids, dithianol, calcipotriol, tacalcitol, ICAM-1 ISIS 2302, ILl 0, daclizumab (anti-TAC) and basiliximab, or A is a therapy chosen from ultraviolet B (UVB), psoralens ultiaviolet A (PUVA) each optionally administered with retinoids, methotrexate or cyclosporin + retinoids.
14. The use according to claim 13 wherein B is
15. Use of one or more active ingredient A together with one or more p38 kinase inhibitor B, optionally combined with conventional excipients and/or carriers, for the manufacture of preparing a pharmaceutical composition wfeefl s-suitable for the treatment ofiftg Crohn's disease wherein A is chosen from one or more steroids, 5-ASA drugs, immunosuppressants, antivirals, biological agents and adhesion molecule inhibitors; and wherein B is chosen from
and
or the pharmaceutically acceptable salts thereof.
16. The use according to claim 15 wherein wherein A is chosen from one or more
5-ASA, methotrexate, azathioprine, budesonide, IL-1 receptor antagonists, etanercept, infliximab, adalimumab (D2E7), CDP 571, lenercept, biological agents directed against targets CD-4, CTLA-4, LFA-1, IL-6, ICAM-1 and C5, IL-10, ISIS 8 , antegren or the compounds:
17. The use according to claim 16 wherein B is
EP03785255A 2002-08-13 2003-08-12 COMBINATION THERAPY WITH p38 MAP KINASE INHIBITORS AND THEIR PHARMACEUTICAL COMPOSITIONS Withdrawn EP1530477A1 (en)

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